Review pubs.acs.org/jnp
Natural Product Primary Sulfonamides and Primary Sulfamates Prashant Mujumdar and Sally-Ann Poulsen* Eskitis Institute for Drug Discovery, Griffith University, Don Young Road, Nathan, Queensland 4111, Australia ABSTRACT: Primary sulfonamide and primary sulfamate functional groups feature prominently in the structures of U.S. FDA-approved drugs. However, the natural product chemical space contains few examples of these well-known zinc-binding chemotypes, with just two primary sulfonamide and five primary sulfamate natural products isolated and characterized to date. One of these natural products was isolated from a marine sponge, with the remainder isolated from Streptomyces species. In this review are outlined for the first time the discovery, isolation, striking breadth of bioactivity, and total synthesis (where available) for this rare group of natural products.
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INTRODUCTION
STRUCTURAL TYPES (−)-Altemicidin (1). As part of a 1989 screening campaign to identify new insecticides and acaricides, 200 actinomycete strains of marine origin were screened using a brine shrimp lethality assay.4 Actinomycetes are prolific producers of bioactive compounds,15 and one strain, Streptomyces sioyaensis SA-1758, from a sample of sea mud from Japan showed potent activity that could be attributed to a new compound, (−)-altemicidin (1). Compound 1 was subsequently produced from a 10 L culture of S. sioyaensis SA-1758, with 232 mg isolated as a white powder following isolation and purification from active fractions.4 The bioactivity for compound 1 was broadly investigated, and it exhibited an LC50 (50% lethal concentration) of 3 μg/mL in the brine shrimp assay, acaricidal activity against mites at ∼10 ppm (to produce a 50% preventative value), and strong inhibition of the growth of two tumor cell lines, murine L1210 lymphoid leukemia and IMC carcinoma, with IC50 (50% inhibitory concentration) values of 0.8 μg/mL (2.12 μM) in both cases. Compound 1 showed no inhibitory activity against a range of Gram-positive and Gram-negative bacteria, mycobacteria, yeasts, and molds, with one exception, a Xanthomonas species, in which it caused mild growth inhibition. The acute toxicity of compound 1 in mice was high, with an LD50 (50% lethal dose) of ∼0.3 mg/kg. Compound 1 was produced through a fermentation process to provide material for the chemical elaboration to the synthesis of mono- and bisacylated derivatives of 1 with various amino acids.16,17 These secondary sulfonamide derivatives were found to be strong inhibitors of isoleucyl, leucyl, and valyl t-RNA synthetases.17 The structure and absolute configuration of compound 1 were determined using a combination of spectroscopic and Xray crystallographic analysis of the natural product and several
Primary sulfonamide (−SO2NH2) and primary sulfamate (−OSO2NH2) groups are well-known zinc-binding groups (ZBGs) that feature in the structure of a selection of ∼26 U.S. FDA-approved drugs and a growing number of experimental drugs.1 These drugs are known to act on a range of molecular targets, including the zinc metalloenzyme carbonic anhydrase, dopamine receptors, ion channels, and solute carriers.1,2 Natural products that contain a primary sulfonamide or primary sulfamate group in their structure are known, but they are rare. A literature search of the Dictionary of Natural Products (DNP) database3 returned two primary sulfonamide and five primary sulfamate natural product hits. The primary sulfonamides are (−)-altemicidin (1), an alkaloid isolated from the actinomycete Streptomyces sioyaensis,4 and psammaplin C (2), a bromotyrosine-cysteine amino acid derivative isolated from the sponge Psammaplysilla purpurea5 (Figure 1). These sulfonamides were reported in 1989 and 1991, respectively.4,5 The primary sulfamate DNP hits identified include the adenosine nucleoside derivatives nucleocidin (3), 5′-Osulfamoyladenosine (4), 5′-O-sulfamoyl-2-chloroadenosine, also known as dealanylascamycin (5), 5′-O-sulfamoyl-2bromoadenosine (6), and the 7-deaza-adenosine derivative 5′O-sulfamoyltubercidin (7) (Figure 1). Sulfamates 4−7 were isolated from various terrestrial actinomycetes (Streptomyces species),6−10 while 3 was discovered in the soil microbe Streptomyces calvus.11,12 Nucleocidin (3) deserves a special mention, as it contains a fluorinated sugar in its structure and so belongs to two families of rare natural products, with fluorinecontaining natural products also exceedingly rare.13,14 An overview of the discovery, total synthesis, and reported bioactivity for natural products 1−7 will be presented in this review. © XXXX American Chemical Society and American Society of Pharmacognosy
Received: December 16, 2014
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Figure 1. Natural product primary sulfonamides: (−)-altemicidin (1) and psammaplin C (2). Natural product primary sulfamates: nucleocidin (3), 5′-O-sulfamoyladenosine (4), 5′-O-sulfamoyl-2-chloroadenosine (5), 5′-O-sulfamoyl-2-bromoadenosine (6), and 5′-O-sulfamoyltubercidin (7).
Scheme 1. Total Synthesis of (−)-Altemicidin (1) As Reported by Kende et al. in 199522
Scheme 2. Approach toward the Synthesis of (−)-Altemicidin (1) by Ohfune and Co-workers24
synthetic derivatives. Compound 1 is an α,α-disubstituted αamino acid comprising a monoterpene-alkaloid skeleton, a 6azaindene moiety with a cis-ring junction, and four successive chiral centers. This compound represents the first reported finding of a cytotoxic alkaloid from a marine actinomycete.4,18−20 The isolation of two secondary sulfonamide analogues that are structurally related to (−)-altemicidin (1) has been reported subsequently from Streptomyces sp. NCIMB 40513.21 The first and only published total synthesis of 1 was reported by Kende and co-workers in 199522 and has been reviewed in detail by both Kang and Ohfune’s teams.23,24 Briefly, a Diels−Alder reaction (8) forms the basis of the
synthetic route, allowing the construction of the 1-amino-2hydroxycyclopentanecarboxylate unit (9) in an endo-selective manner as a single diastereomer, with this followed by 26 subsequent steps to give (−)-altemicidin (1) (Scheme 1).22 Ohfune and co-workers also described an approach toward the total synthesis of optically active 1 that employed the Strecker synthesis of α-amino nitriles 11 and 12 (1:1) from 2acyloxybicyclo[3.3.0]octanedione (10).24 The cis/syn/cis isomer 11 comprised the desired configuration of (−)-altemicidin (1), and this intermediate was carried forward to amino acid 13 by ozone oxidation followed by acid hydrolysis (Scheme 2). The completed synthesis of 1 has, however, not been reported by B
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Scheme 3. Synthesis of the Core Framework of (−)-Altemicidin (1) via Intermediate 19, As Reported by Fukuyama et al. in 200825
Figure 2. Psammaplins A, B, and D share the bromotyrosine core of compound 2 but lack a primary sulfonamide group.
Scheme 4. Total Synthesis of Psammaplin C (2) As Reported by Harburn et al. in 201227
this group, nor were specific experimental details of their synthesis provided.24 An advanced intermediate toward the stereoselective synthesis of compound 1 was reported by Fukuyama and coworkers, in 2008.25 This intermediate, compound 19, comprised the four stereocenters, vinylogous urea unit, and 6azaindene core of compound 1. The rhodium-carbenoidassisted C−H insertion reaction of diazoester 14 provided the bicyclo[3.3.0] core, 15 (Scheme 3). Next, a 13-step
transformation of 15 to compound 16 was followed by the stereoselective construction of the β-hydroxy α,α-disubstituted α-amino acid 17 by treatment of 16 with camphorsulfonic acid (CSA) and quinolone. Compound 18 was generated in a further seven steps from 17. Treatment of 18 with base hydrolyzed the oxazolidinone ring; then Dess−Martin oxidation gave the corresponding aldehyde, and finally conversion of the nitrile functionality to a primary amide C
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Scheme 5. Total Synthesis of Nucleocidin (3) Reported by Moffatt et al. in 197632,33
μg/mL).27 In this study, compound 2 showed no pronounced cytotoxicity when screened against NCI-60, a set of human tumor cell lines at the U.S. National Cancer Institute that represents leukemia, melanoma, and cancers of the lung, colon, brain, ovary, breast, prostate, and kidney.27 Nucleocidin (3). Nucleocidin (3) was first identified in 1956 as an antibiotic compound from the fermentation broth of Streptomyces calvus, a microbe isolated from an Indian soil sample.11,12 Compound 3 showed potent activity against trypanosomal parasites11,12 in addition to broad antibacterial activity against Gram-positive and Gram-negative bacteria, including some pathogenic bacteria such as Streptococcus pyogenes var. hemolyticus.28,29 The chemical structure corresponding to the discovery of 3 was for many years attributed incorrectly. However, following access to 19F NMR spectroscopy and mass spectrometry methods, the structure of nucleocidin was accurately revised in 1969.30 The compound comprises a covalently bound fluorine at the 4′-carbon of the ribose moiety of 5′-O-sulfamoyladenosine (4) and is one of the first known fluorinated natural products.30 Owing to partial structural similarities to the known protein synthesis inhibitor antibiotic puromycin (also an adenosine derivative), natural product 3 was investigated in protein synthesis assays and found to be more potent than puromycin in blocking protein synthesis. Insufficient compound from isolation efforts, however, prevented detailed studies of 3.31 A total synthesis for 3 was reported by Moffatt and coworkers in 1976, 20 years after this compound was first isolated.32−34 The synthetic route commenced with the sequential conversion of 2′,3′-O-isopropylidine-protected adenosine (24) to the N6-benzoyl derivative 25 and then the 5′O-mesyl derivative 26 (Scheme 5). Crude 26 was next treated with potassium tert-butoxide to generate the furanose olefin 27, and reaction of this product with benzoyl chloride in pyridine gave the N6,N6-dibenzoyl olefin 28. Several methods for the stereospecific addition of fluorine at C-4′ of 28 were
group with Parkin’s catalyst afforded the advanced intermediate, compound 19. Psammaplin C (2). The psammaplin compound class comprises a functionalized bromotyrosine-cysteine framework. The primary sulfonamide natural product, psammaplin C (2), was isolated in 1991 from the sponge Pseudoceratina purpurea along with related but nonprimary sulfonamide psammaplin structures, psammaplins A, B, and D (Figure 2).5 The structure of compound 2 was confirmed following a detailed spectroscopic analysis, with the characteristic primary sulfonamide functional group appearing as a distinct structural feature that was absent in the other members of the psammaplin family.5,26 A partial biosynthesis for 2 was proposed in which a bromo oxime functionalized tyrosine condensed with a rearranged cysteine to form a disulfide, which is the precursor to the sulfonamide moiety of 2. The first bioactivity study for compound 2 alongside the other psammaplins was reported in 2003. Compound 2 had no effect on inhibition of histone deacetylase (HDAC) at the test concentrations used (IC50 > 40 nM). However, owing to insufficient material being available, no follow-up or additional bioactivity testing was able to be assessed at that point, with the other psammaplins available in sufficient quantity to be studied in greater detail.26 A total synthesis for sulfonamide 2 from readily available starting materials was described by Harburn and co-workers in 2012 (Scheme 4).27 The reaction of 4-benzyloxy-3-bromobenzaldehyde (20) with rhodanine formed the benzylidenerhodanine adduct 21. This adduct was subjected to basic hydrolysis, the reaction was acidified, and oximation with Obenzylhydroxylamine was carried out to generate the O-benzylprotected oxime-carboxylic acid 22.27 Amide coupling of 22 with β-aminoethanesulfonamide furnished the O-benzylprotected psammaplin C (23). Finally, Lewis acid-assisted removal of the benzyl groups of 23 afforded the natural product compound 2. The antibacterial and antifungal properties of compound 2 were assessed and found to have no activity (>128 D
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enzyme),43 M. tuberculosis adenylate-forming enzyme MbtA,44 siderophore biosynthesis in M. tuberculosis,45 and histidine triad proteins (enzymes that act as hydrolases/transferases on nucleoside monophosphate substrates). In all cases, low activity was observed for 4, while analogues substituted on the sulfamate nitrogen of 4 showed good activity.46 Compound 4 and the chlorinated sulfamate nucleoside 5 (see below) were also reported to inhibit serotonin-induced platelet aggregation, but were ineffective inhibitors of adenosine diphosphate (ADP)-induced platelet aggregation.47 This activity has promise for the future development of antithrombotic agents, although further analysis is yet to appear in the literature.47,48 The isolation and proposed structure for 5′-O-sulfamoyl-2chloroadenosine [5, also known as dealanylascamycin (DAA) or AT-265] from a soil Streptomyces sp. was reported in 1982.48 This compound was reisolated in 1984 from a Streptomyces sp. soil sample, and its absolute configuration verified by derivatization of the 5′-O-sulfamoyl group.49 Compound 5 exhibited high toxicity to mice.49 Ascamycin, a derivative of 5 in which the sulfamate nitrogen is masked with an alanine moiety, was also isolated from a Streptomyces sp. soil sample. In contrast to 5, this alanine derivative displayed selective microbial activity against Xanthomonas citri (MIC 0.4 μg/mL) but with low to no activity against other test microbes. An interesting experiment in which ascamycin was incubated with X. citri resulted in dealanylation of ascamycin to form 5 in quantitative yield, while this conversion was not observed in the remaining panel of microbes. The susceptibility of X. citri to ascamycin was thus proposed as being associated with the expression of a dealanylating enzyme on the cell membrane, with this enzyme absent from organisms that are resistant to ascamycin.50 Compound 5 was found to inhibit both Gram-positive and Gram-negative bacteria via blocking protein synthesis, although the molecular target of this observation was not further investigated.51 Herbicidal activity of compound 5, specifically inhibition of plant growth with respect to root or stem and coleoptile length (expressed as ID50 values in μm), on different mono- and dicotyledonous plant species has been reported.52 In these studies, the phytotoxic effects of 5 were compared to that of the known herbicidal protein synthesis inhibitors, cycloheximide and chloramphenicol, with compound 5 proving to be 10- to 100-fold more active than these standard compounds.52 In another study, the herbicidal activity of 5 against a range of weeds was shown to be extremely potent, at 16% inhibition at 1 nM).42 Additional bioactivities that have been investigated for sulfamate 4 include in vitro inhibition of each of Mycobacterium tuberculosis FadD28 (fatty acid adenylating E
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Scheme 6. Standard Synthetic Approach Used for the 5′-O-Sulfamoyladenosines, Compounds 4 and 56,42,47
Scheme 7. Direct Synthesis of 5′-O-Sulfamoyladenosine (4) and Dealanylascamycin (5) As Reported by Kristinsson et al. in 19956
Scheme 8. Synthesis of Natural Product 4 via a 5′-O-Tributyltin Ether Intermediate46,53
Scheme 9. Synthesis of Natural Product 4 via a Combined Global Silyl Ether Protecting Group and 5′-O-Tributyltin Ether Intermediate45,54
nucleophilic base (such as NaH) provided the sulfamoylated intermediates 40 and 41. Last, the 2′,3′-isopropylidine groups of 40 and 41 were removed by treatment with aqueous acid (e.g., TFA or formic acid) to generate the target sulfamates 4 and 5 (Scheme 6). Kristinsson and co-workers made substantial efforts to optimize the standard sulfamoylation conditions and found that the use of a weak base in place of NaH, specifically
Sulfamoylation of the 5′-OH group of 2′,3′-acetonideprotected nucleosides is the standard synthetic approach used in the synthesis of 5′-O-sulfamoyl nucleosides.6,42,47 To synthesize sulfamates 4 and 5, the 2′,3′-hydroxy-groupprotected nucleosides 38 and 39 were prepared from the parent nucleosides, 36 and 37, respectively.6 Next, sulfamoylation using sulfamoyl chloride together with a strong nonF
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Scheme 10. Proposed Synthetic Route toward 5′-O-Sulfamoyltubercidin (7)
CaCO3 or imidazole in dimethylformamide (DMF) or Nmethyl-2-pyrrolidone (NMP), enhanced significantly both the rate of formation and yield of the sulfamoylation products.6 Furthermore, they found that direct sulfamoylation of the unprotected nucleosides 36 and 37 could be achieved with CaCO3 as base. Using this direct approach, compounds 4 and 5 were formed as the major products, with 2′-O-sulfamoyl and 3′O-sulfamoyl derivatives as minor products (Scheme 7).6 Alternative methods to the standard approach for the synthesis of nucleoside sulfamates have been described wherein a 5′-O-tributyltin ether nucleoside is formed from a 2′,3′-OHprotected adenosine. In the first method, the 5′-O-tributyltin ether intermediate, 42, was obtained by refluxing an acetonideprotected adenosine (38) and bis(tributyltin) oxide in benzene under argon. Without any isolation of 42, the reaction mixture was cooled to 5 °C and treated with a solution of sulfamoyl chloride in dioxane to generate the sulfamate 43. This step was followed by removal of the acetonide-protecting group to give the natural product 4 (Scheme 8).46 The syntheses of 5′-Osulfamoyl-N-aminoacyl analogues of the natural product 5 were reported using a similar approach. In the second method, the synthesis of natural product 4 was carried out by global silylation of the hydroxy groups of adenosine with TBDMSCl, followed by the selective removal of the 5′-O-TBDMS ether (44) and conversion of 44 to the 5′-O-tributyltin ether nucleoside 45, which was isolated. Sulfamoylation of 45 provided the 2′,3′-bis-O-TBDMS-protected sulfamate 46. Removal of the TBDMS ether protecting groups of 46 with tetrabutylammonium fluoride gave the nucleoside sulfamate 4 (Scheme 9).45,54 5′-O-Sulfamoyltubercidin (7). 5′-O-Sulfamoyltubercidin (7) has been reported to exhibit insecticidal and acaricidal bioactivity.55 While the biological production of 7 is known, to the best of our knowledge there is no reported total synthesis of this compound. The synthesis of 5′-O-sulfamoyl-N-salicyltubercidin derivatives from tubercidin (47) is however known.56 In the synthesis of these compounds, acetonation of tubercidin 47 gave the 2′,3′-hydroxy-group-protected nucleocidin 48, which underwent sulfamoylation at the 5′-OH group with NaH in dimethyl ether (DME) to afford 49.56 Compound 49 could presumably be converted to 7, but this final step was not carried out (Scheme 10).
medicine, it will be of interest to comprehensively characterize this sparsely populated area of natural product chemical space in the search for drug-like compounds.57 Specifically, the biosynthesis for all these compounds is unknown, the total synthesis for some compounds is incomplete, and the bioactivity reported is variable. The synthesis of these rare natural products and their biological investigation through exposure to comprehensive screening campaigns is the focus of current efforts in our research group.
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AUTHOR INFORMATION
Corresponding Author
*Tel: +61-7-37357825. Fax: +61-7-37356001. E-mail: s. poulsen@griffith.edu.au. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank the Australian Research Council (grant numbers DP110100071 and FT10100185 to S.-A.P.) and Griffith University (Ph.D. scholarship to P.M.). We thank Prof. I. Jenkins for helpful discussions.
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REFERENCES
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CONCLUSIONS Natural products that contain a primary sulfonamide or primary sulfamate group in their structure are known. However, these are rare, with just two primary sulfonamide and five primary sulfamate natural products reported to date. One of the natural products was isolated from a marine sponge and may in fact be a microbial product, while the remainder were isolated from a range of terrestrial Streptomyces species. Given the importance of the sulfonamide and sulfamate functional groups to G
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(47) Gough, G. R.; Nobbs, D. M.; Middleton, J. C.; Penglis-Caredes, F.; Maguire, M. H. J. Med. Chem. 1978, 21, 520−525. (48) Takahashi, E.; Beppu, T. J. Antibiot. 1982, 35, 939−947. (49) Isono, K.; U, M.; Kusakabe, H.; Miyata, N.; Koyama, T.; Ubukata, M.; Sethi, S. K.; McCloskey, J. A. J. Antibiot. 1984, 37, 670− 672. (50) Ubukata, M.; O, H.; Magae, J.; Isono, K. Agric. Biol. Chem. 1988, 52, 1117−1122. (51) Osada, H.; Isono, K. Antimicrob. Agents Chemother. 1985, 27, 230−233. (52) Scacchi, A.; B, R.; Cassani, G.; Nielsen, E. Pestic. Biochem. Physiol. 1994, 50, 149−158. (53) Castro-Pichel, J.; García-López, M. T.; De las Heras, F. G. Tetrahedron 1987, 43, 383−389. (54) Tan, D. S.; Quadri, L. E. N.; Ryu, J.-S.; Cisar, J. S.; Ferreras, J. A.; Lu, X. WO 2006/113615 A2, 2006. (55) Imamura, K.; Iwata, M.; Ajito, Y.; Shiomura, T.; Endo, K.; Hirose, T. Jap. Pat. JP 03098593A 19910424, 1991. (56) Neres, J.; Labello, N. P.; Somu, R. V.; Boshoff, H. I.; Wilson, D. J.; Vannada, J.; Chen, L.; Barry, C. E.; Bennett, E. M.; Aldrich, C. C. J. Med. Chem. 2008, 51, 5349−5370. (57) Poulsen, S.-A.; Davis, R. A. Sub-cell. Biochem. 2014, 75, 325− 347.
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Natural Product Primary Sulfonamides and Primary Sulfamates Prashant Mujumdar and Sally-Ann Poulsen* Eskitis Institute for Drug Discovery, Griffith University, Don Young Road, Nathan, Queensland 4111, Australia ABSTRACT: Primary sulfonamide and primary sulfamate functional groups feature prominently in the structures of U.S. FDA-approved drugs. However, the natural product chemical space contains few examples of these well-known zinc-binding chemotypes, with just two primary sulfonamide and five primary sulfamate natural products isolated and characterized to date. One of these natural products was isolated from a marine sponge, with the remainder isolated from Streptomyces species. In this review are outlined for the first time the discovery, isolation, striking breadth of bioactivity, and total synthesis (where available) for this rare group of natural products.
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INTRODUCTION
STRUCTURAL TYPES (−)-Altemicidin (1). As part of a 1989 screening campaign to identify new insecticides and acaricides, 200 actinomycete strains of marine origin were screened using a brine shrimp lethality assay.4 Actinomycetes are prolific producers of bioactive compounds,15 and one strain, Streptomyces sioyaensis SA-1758, from a sample of sea mud from Japan showed potent activity that could be attributed to a new compound, (−)-altemicidin (1). Compound 1 was subsequently produced from a 10 L culture of S. sioyaensis SA-1758, with 232 mg isolated as a white powder following isolation and purification from active fractions.4 The bioactivity for compound 1 was broadly investigated, and it exhibited an LC50 (50% lethal concentration) of 3 μg/mL in the brine shrimp assay, acaricidal activity against mites at ∼10 ppm (to produce a 50% preventative value), and strong inhibition of the growth of two tumor cell lines, murine L1210 lymphoid leukemia and IMC carcinoma, with IC50 (50% inhibitory concentration) values of 0.8 μg/mL (2.12 μM) in both cases. Compound 1 showed no inhibitory activity against a range of Gram-positive and Gram-negative bacteria, mycobacteria, yeasts, and molds, with one exception, a Xanthomonas species, in which it caused mild growth inhibition. The acute toxicity of compound 1 in mice was high, with an LD50 (50% lethal dose) of ∼0.3 mg/kg. Compound 1 was produced through a fermentation process to provide material for the chemical elaboration to the synthesis of mono- and bisacylated derivatives of 1 with various amino acids.16,17 These secondary sulfonamide derivatives were found to be strong inhibitors of isoleucyl, leucyl, and valyl t-RNA synthetases.17 The structure and absolute configuration of compound 1 were determined using a combination of spectroscopic and Xray crystallographic analysis of the natural product and several
Primary sulfonamide (−SO2NH2) and primary sulfamate (−OSO2NH2) groups are well-known zinc-binding groups (ZBGs) that feature in the structure of a selection of ∼26 U.S. FDA-approved drugs and a growing number of experimental drugs.1 These drugs are known to act on a range of molecular targets, including the zinc metalloenzyme carbonic anhydrase, dopamine receptors, ion channels, and solute carriers.1,2 Natural products that contain a primary sulfonamide or primary sulfamate group in their structure are known, but they are rare. A literature search of the Dictionary of Natural Products (DNP) database3 returned two primary sulfonamide and five primary sulfamate natural product hits. The primary sulfonamides are (−)-altemicidin (1), an alkaloid isolated from the actinomycete Streptomyces sioyaensis,4 and psammaplin C (2), a bromotyrosine-cysteine amino acid derivative isolated from the sponge Psammaplysilla purpurea5 (Figure 1). These sulfonamides were reported in 1989 and 1991, respectively.4,5 The primary sulfamate DNP hits identified include the adenosine nucleoside derivatives nucleocidin (3), 5′-Osulfamoyladenosine (4), 5′-O-sulfamoyl-2-chloroadenosine, also known as dealanylascamycin (5), 5′-O-sulfamoyl-2bromoadenosine (6), and the 7-deaza-adenosine derivative 5′O-sulfamoyltubercidin (7) (Figure 1). Sulfamates 4−7 were isolated from various terrestrial actinomycetes (Streptomyces species),6−10 while 3 was discovered in the soil microbe Streptomyces calvus.11,12 Nucleocidin (3) deserves a special mention, as it contains a fluorinated sugar in its structure and so belongs to two families of rare natural products, with fluorinecontaining natural products also exceedingly rare.13,14 An overview of the discovery, total synthesis, and reported bioactivity for natural products 1−7 will be presented in this review. © XXXX American Chemical Society and American Society of Pharmacognosy
Received: December 16, 2014
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Figure 1. Natural product primary sulfonamides: (−)-altemicidin (1) and psammaplin C (2). Natural product primary sulfamates: nucleocidin (3), 5′-O-sulfamoyladenosine (4), 5′-O-sulfamoyl-2-chloroadenosine (5), 5′-O-sulfamoyl-2-bromoadenosine (6), and 5′-O-sulfamoyltubercidin (7).
Scheme 1. Total Synthesis of (−)-Altemicidin (1) As Reported by Kende et al. in 199522
Scheme 2. Approach toward the Synthesis of (−)-Altemicidin (1) by Ohfune and Co-workers24
synthetic derivatives. Compound 1 is an α,α-disubstituted αamino acid comprising a monoterpene-alkaloid skeleton, a 6azaindene moiety with a cis-ring junction, and four successive chiral centers. This compound represents the first reported finding of a cytotoxic alkaloid from a marine actinomycete.4,18−20 The isolation of two secondary sulfonamide analogues that are structurally related to (−)-altemicidin (1) has been reported subsequently from Streptomyces sp. NCIMB 40513.21 The first and only published total synthesis of 1 was reported by Kende and co-workers in 199522 and has been reviewed in detail by both Kang and Ohfune’s teams.23,24 Briefly, a Diels−Alder reaction (8) forms the basis of the
synthetic route, allowing the construction of the 1-amino-2hydroxycyclopentanecarboxylate unit (9) in an endo-selective manner as a single diastereomer, with this followed by 26 subsequent steps to give (−)-altemicidin (1) (Scheme 1).22 Ohfune and co-workers also described an approach toward the total synthesis of optically active 1 that employed the Strecker synthesis of α-amino nitriles 11 and 12 (1:1) from 2acyloxybicyclo[3.3.0]octanedione (10).24 The cis/syn/cis isomer 11 comprised the desired configuration of (−)-altemicidin (1), and this intermediate was carried forward to amino acid 13 by ozone oxidation followed by acid hydrolysis (Scheme 2). The completed synthesis of 1 has, however, not been reported by B
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Scheme 3. Synthesis of the Core Framework of (−)-Altemicidin (1) via Intermediate 19, As Reported by Fukuyama et al. in 200825
Figure 2. Psammaplins A, B, and D share the bromotyrosine core of compound 2 but lack a primary sulfonamide group.
Scheme 4. Total Synthesis of Psammaplin C (2) As Reported by Harburn et al. in 201227
this group, nor were specific experimental details of their synthesis provided.24 An advanced intermediate toward the stereoselective synthesis of compound 1 was reported by Fukuyama and coworkers, in 2008.25 This intermediate, compound 19, comprised the four stereocenters, vinylogous urea unit, and 6azaindene core of compound 1. The rhodium-carbenoidassisted C−H insertion reaction of diazoester 14 provided the bicyclo[3.3.0] core, 15 (Scheme 3). Next, a 13-step
transformation of 15 to compound 16 was followed by the stereoselective construction of the β-hydroxy α,α-disubstituted α-amino acid 17 by treatment of 16 with camphorsulfonic acid (CSA) and quinolone. Compound 18 was generated in a further seven steps from 17. Treatment of 18 with base hydrolyzed the oxazolidinone ring; then Dess−Martin oxidation gave the corresponding aldehyde, and finally conversion of the nitrile functionality to a primary amide C
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Scheme 5. Total Synthesis of Nucleocidin (3) Reported by Moffatt et al. in 197632,33
μg/mL).27 In this study, compound 2 showed no pronounced cytotoxicity when screened against NCI-60, a set of human tumor cell lines at the U.S. National Cancer Institute that represents leukemia, melanoma, and cancers of the lung, colon, brain, ovary, breast, prostate, and kidney.27 Nucleocidin (3). Nucleocidin (3) was first identified in 1956 as an antibiotic compound from the fermentation broth of Streptomyces calvus, a microbe isolated from an Indian soil sample.11,12 Compound 3 showed potent activity against trypanosomal parasites11,12 in addition to broad antibacterial activity against Gram-positive and Gram-negative bacteria, including some pathogenic bacteria such as Streptococcus pyogenes var. hemolyticus.28,29 The chemical structure corresponding to the discovery of 3 was for many years attributed incorrectly. However, following access to 19F NMR spectroscopy and mass spectrometry methods, the structure of nucleocidin was accurately revised in 1969.30 The compound comprises a covalently bound fluorine at the 4′-carbon of the ribose moiety of 5′-O-sulfamoyladenosine (4) and is one of the first known fluorinated natural products.30 Owing to partial structural similarities to the known protein synthesis inhibitor antibiotic puromycin (also an adenosine derivative), natural product 3 was investigated in protein synthesis assays and found to be more potent than puromycin in blocking protein synthesis. Insufficient compound from isolation efforts, however, prevented detailed studies of 3.31 A total synthesis for 3 was reported by Moffatt and coworkers in 1976, 20 years after this compound was first isolated.32−34 The synthetic route commenced with the sequential conversion of 2′,3′-O-isopropylidine-protected adenosine (24) to the N6-benzoyl derivative 25 and then the 5′O-mesyl derivative 26 (Scheme 5). Crude 26 was next treated with potassium tert-butoxide to generate the furanose olefin 27, and reaction of this product with benzoyl chloride in pyridine gave the N6,N6-dibenzoyl olefin 28. Several methods for the stereospecific addition of fluorine at C-4′ of 28 were
group with Parkin’s catalyst afforded the advanced intermediate, compound 19. Psammaplin C (2). The psammaplin compound class comprises a functionalized bromotyrosine-cysteine framework. The primary sulfonamide natural product, psammaplin C (2), was isolated in 1991 from the sponge Pseudoceratina purpurea along with related but nonprimary sulfonamide psammaplin structures, psammaplins A, B, and D (Figure 2).5 The structure of compound 2 was confirmed following a detailed spectroscopic analysis, with the characteristic primary sulfonamide functional group appearing as a distinct structural feature that was absent in the other members of the psammaplin family.5,26 A partial biosynthesis for 2 was proposed in which a bromo oxime functionalized tyrosine condensed with a rearranged cysteine to form a disulfide, which is the precursor to the sulfonamide moiety of 2. The first bioactivity study for compound 2 alongside the other psammaplins was reported in 2003. Compound 2 had no effect on inhibition of histone deacetylase (HDAC) at the test concentrations used (IC50 > 40 nM). However, owing to insufficient material being available, no follow-up or additional bioactivity testing was able to be assessed at that point, with the other psammaplins available in sufficient quantity to be studied in greater detail.26 A total synthesis for sulfonamide 2 from readily available starting materials was described by Harburn and co-workers in 2012 (Scheme 4).27 The reaction of 4-benzyloxy-3-bromobenzaldehyde (20) with rhodanine formed the benzylidenerhodanine adduct 21. This adduct was subjected to basic hydrolysis, the reaction was acidified, and oximation with Obenzylhydroxylamine was carried out to generate the O-benzylprotected oxime-carboxylic acid 22.27 Amide coupling of 22 with β-aminoethanesulfonamide furnished the O-benzylprotected psammaplin C (23). Finally, Lewis acid-assisted removal of the benzyl groups of 23 afforded the natural product compound 2. The antibacterial and antifungal properties of compound 2 were assessed and found to have no activity (>128 D
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enzyme),43 M. tuberculosis adenylate-forming enzyme MbtA,44 siderophore biosynthesis in M. tuberculosis,45 and histidine triad proteins (enzymes that act as hydrolases/transferases on nucleoside monophosphate substrates). In all cases, low activity was observed for 4, while analogues substituted on the sulfamate nitrogen of 4 showed good activity.46 Compound 4 and the chlorinated sulfamate nucleoside 5 (see below) were also reported to inhibit serotonin-induced platelet aggregation, but were ineffective inhibitors of adenosine diphosphate (ADP)-induced platelet aggregation.47 This activity has promise for the future development of antithrombotic agents, although further analysis is yet to appear in the literature.47,48 The isolation and proposed structure for 5′-O-sulfamoyl-2chloroadenosine [5, also known as dealanylascamycin (DAA) or AT-265] from a soil Streptomyces sp. was reported in 1982.48 This compound was reisolated in 1984 from a Streptomyces sp. soil sample, and its absolute configuration verified by derivatization of the 5′-O-sulfamoyl group.49 Compound 5 exhibited high toxicity to mice.49 Ascamycin, a derivative of 5 in which the sulfamate nitrogen is masked with an alanine moiety, was also isolated from a Streptomyces sp. soil sample. In contrast to 5, this alanine derivative displayed selective microbial activity against Xanthomonas citri (MIC 0.4 μg/mL) but with low to no activity against other test microbes. An interesting experiment in which ascamycin was incubated with X. citri resulted in dealanylation of ascamycin to form 5 in quantitative yield, while this conversion was not observed in the remaining panel of microbes. The susceptibility of X. citri to ascamycin was thus proposed as being associated with the expression of a dealanylating enzyme on the cell membrane, with this enzyme absent from organisms that are resistant to ascamycin.50 Compound 5 was found to inhibit both Gram-positive and Gram-negative bacteria via blocking protein synthesis, although the molecular target of this observation was not further investigated.51 Herbicidal activity of compound 5, specifically inhibition of plant growth with respect to root or stem and coleoptile length (expressed as ID50 values in μm), on different mono- and dicotyledonous plant species has been reported.52 In these studies, the phytotoxic effects of 5 were compared to that of the known herbicidal protein synthesis inhibitors, cycloheximide and chloramphenicol, with compound 5 proving to be 10- to 100-fold more active than these standard compounds.52 In another study, the herbicidal activity of 5 against a range of weeds was shown to be extremely potent, at 16% inhibition at 1 nM).42 Additional bioactivities that have been investigated for sulfamate 4 include in vitro inhibition of each of Mycobacterium tuberculosis FadD28 (fatty acid adenylating E
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Scheme 6. Standard Synthetic Approach Used for the 5′-O-Sulfamoyladenosines, Compounds 4 and 56,42,47
Scheme 7. Direct Synthesis of 5′-O-Sulfamoyladenosine (4) and Dealanylascamycin (5) As Reported by Kristinsson et al. in 19956
Scheme 8. Synthesis of Natural Product 4 via a 5′-O-Tributyltin Ether Intermediate46,53
Scheme 9. Synthesis of Natural Product 4 via a Combined Global Silyl Ether Protecting Group and 5′-O-Tributyltin Ether Intermediate45,54
nucleophilic base (such as NaH) provided the sulfamoylated intermediates 40 and 41. Last, the 2′,3′-isopropylidine groups of 40 and 41 were removed by treatment with aqueous acid (e.g., TFA or formic acid) to generate the target sulfamates 4 and 5 (Scheme 6). Kristinsson and co-workers made substantial efforts to optimize the standard sulfamoylation conditions and found that the use of a weak base in place of NaH, specifically
Sulfamoylation of the 5′-OH group of 2′,3′-acetonideprotected nucleosides is the standard synthetic approach used in the synthesis of 5′-O-sulfamoyl nucleosides.6,42,47 To synthesize sulfamates 4 and 5, the 2′,3′-hydroxy-groupprotected nucleosides 38 and 39 were prepared from the parent nucleosides, 36 and 37, respectively.6 Next, sulfamoylation using sulfamoyl chloride together with a strong nonF
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Scheme 10. Proposed Synthetic Route toward 5′-O-Sulfamoyltubercidin (7)
CaCO3 or imidazole in dimethylformamide (DMF) or Nmethyl-2-pyrrolidone (NMP), enhanced significantly both the rate of formation and yield of the sulfamoylation products.6 Furthermore, they found that direct sulfamoylation of the unprotected nucleosides 36 and 37 could be achieved with CaCO3 as base. Using this direct approach, compounds 4 and 5 were formed as the major products, with 2′-O-sulfamoyl and 3′O-sulfamoyl derivatives as minor products (Scheme 7).6 Alternative methods to the standard approach for the synthesis of nucleoside sulfamates have been described wherein a 5′-O-tributyltin ether nucleoside is formed from a 2′,3′-OHprotected adenosine. In the first method, the 5′-O-tributyltin ether intermediate, 42, was obtained by refluxing an acetonideprotected adenosine (38) and bis(tributyltin) oxide in benzene under argon. Without any isolation of 42, the reaction mixture was cooled to 5 °C and treated with a solution of sulfamoyl chloride in dioxane to generate the sulfamate 43. This step was followed by removal of the acetonide-protecting group to give the natural product 4 (Scheme 8).46 The syntheses of 5′-Osulfamoyl-N-aminoacyl analogues of the natural product 5 were reported using a similar approach. In the second method, the synthesis of natural product 4 was carried out by global silylation of the hydroxy groups of adenosine with TBDMSCl, followed by the selective removal of the 5′-O-TBDMS ether (44) and conversion of 44 to the 5′-O-tributyltin ether nucleoside 45, which was isolated. Sulfamoylation of 45 provided the 2′,3′-bis-O-TBDMS-protected sulfamate 46. Removal of the TBDMS ether protecting groups of 46 with tetrabutylammonium fluoride gave the nucleoside sulfamate 4 (Scheme 9).45,54 5′-O-Sulfamoyltubercidin (7). 5′-O-Sulfamoyltubercidin (7) has been reported to exhibit insecticidal and acaricidal bioactivity.55 While the biological production of 7 is known, to the best of our knowledge there is no reported total synthesis of this compound. The synthesis of 5′-O-sulfamoyl-N-salicyltubercidin derivatives from tubercidin (47) is however known.56 In the synthesis of these compounds, acetonation of tubercidin 47 gave the 2′,3′-hydroxy-group-protected nucleocidin 48, which underwent sulfamoylation at the 5′-OH group with NaH in dimethyl ether (DME) to afford 49.56 Compound 49 could presumably be converted to 7, but this final step was not carried out (Scheme 10).
medicine, it will be of interest to comprehensively characterize this sparsely populated area of natural product chemical space in the search for drug-like compounds.57 Specifically, the biosynthesis for all these compounds is unknown, the total synthesis for some compounds is incomplete, and the bioactivity reported is variable. The synthesis of these rare natural products and their biological investigation through exposure to comprehensive screening campaigns is the focus of current efforts in our research group.
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AUTHOR INFORMATION
Corresponding Author
*Tel: +61-7-37357825. Fax: +61-7-37356001. E-mail: s. poulsen@griffith.edu.au. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank the Australian Research Council (grant numbers DP110100071 and FT10100185 to S.-A.P.) and Griffith University (Ph.D. scholarship to P.M.). We thank Prof. I. Jenkins for helpful discussions.
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REFERENCES
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CONCLUSIONS Natural products that contain a primary sulfonamide or primary sulfamate group in their structure are known. However, these are rare, with just two primary sulfonamide and five primary sulfamate natural products reported to date. One of the natural products was isolated from a marine sponge and may in fact be a microbial product, while the remainder were isolated from a range of terrestrial Streptomyces species. Given the importance of the sulfonamide and sulfamate functional groups to G
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