Bioorganic & Medicinal Chemistry Letters 25 (2015) 184–187
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl
Synthesis and biological evaluation of ( )-6-Odesmethylcryptopleurine and analogs Frédéric Liéby-Muller ⇑, Frédéric Marion, Philippe Schmitt, Jean-Philippe Annereau, Anna Kruczynski, Nicolas Guilbaud, Christian Bailly Institut de Recherche Pierre Fabre, CRDPF/CROE, 3 avenue Hubert Curien, BP 13562, 31035 Toulouse Cedex 1, France
a r t i c l e
i n f o
Article history: Received 29 September 2014 Revised 27 November 2014 Accepted 28 November 2014 Available online 6 December 2014 Keywords: Phenanthroquinolizidine alkaloid ( )-Cryptopleurine Cytotoxicity
a b s t r a c t ( )-Cryptopleurine 1 is one of the most potent anti-proliferative member of the phenanthroquinolizidine class of alkaloids. We report here the synthesis of ( )-6-O-desmethylcryptopleurine ( )-2 and ( )-6-Odesmethyl-(15R)-hydroxycryptopleurine ( )-4 in their enantiomerically enriched form through a convergent synthetic route, where the chirality is introduced by the use of commercially available (R)-methyl piperidine-2-carboxylate hydrochloride 17. Anti-proliferative activities of these compounds were evaluated on a panel of four cancer cell lines, revealing that compounds ( )-2 and ( )-4 are potent cytotoxic compared to cryptopleurine. Ó 2014 Elsevier Ltd. All rights reserved.
( )-Antofine A and ( )-cryptopleurine ( )-1 are plant metabolites belonging, respectively, to the phenanthroindolizidine and phenanthroquinolizidine class of alkaloids. Their isolation from various plant species,1 as well as their syntheses have been well described.2 These compounds are known to exhibit high anti-proliferative activities against several cancer cell lines, showing IC50 values in the low nanomolar range for cryptopleurine and around 10 8 M for antofine (Fig. 1). ( )-6-O-Desmethylantofine B, another closely related natural analog of antofine has gained attention more recently due to the significant improvement of activity provided by the sole loss of a methyl group.3 Based on this observation, we hypothesized that applying this specific substitution pattern by removing the 6-Omethyl of ( )-1 should lead to a more potent derivative.4 So, we wish to report here the total synthesis of ( )-6-O-desmethyl-cryptopleurine ( )-2 and its antiproliferative activities on a panel of four cancer cell lines. Both analogs 3 and ( )-4, obtained during the synthetic process, were also evaluated. The synthesis of compounds ( )-2 and ( )-4 is based on work previously reported by Wang et al.,2 and is depicted on Scheme 1. Condensation of commercially available aldehyde 5 and benzoic acid 6 afforded compound 7. Subsequent esterification with methanol in the presence of sulfuric acid led to 8. At this stage, we had to protect the phenol group. First attempts using a benzyl protecting group, as previously described,2b led, in our hands, to a poorly ⇑ Corresponding author. Tel.: +33 5 34 50 69 38; fax: +33 5 34 50 30 54. E-mail address: [email protected] (F. Liéby-Muller). http://dx.doi.org/10.1016/j.bmcl.2014.11.086 0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.
reproducible synthesis, notably due to the lack of solubility of the intermediates. The use of a tert-butyldiphenylsilyl ether (TBDPS) proved to be the better protection strategy to pursue a tractable
O
HO N (R)
Increase in potency
N (R)
H
H
O
O O
O
(-)-antofine A IC50 (A549) = 10 nM
(-)-6- O-desmethylantofine B IC50 (A549) = 1 nM
Increase in potency O
HO N (R)
N
Potency ?
(R)
H O
H O
O (-)-cryptopleurine (-)-1 IC50 (A549) = 1.9 nM
O (-)-6- O-desmethylcryptopleurine (-)-2
Figure 1. Chemical structures of A, B, ( )-1, ( )-2 and ( )-4.
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F. Liéby-Muller et al. / Bioorg. Med. Chem. Lett. 25 (2015) 184–187
O
O
O
H
O
HO
O
HO
O
O
TBDPS
OH
O
O
a
b
O
c
O O
5
O
O
OH
O
6
7
TBDPS
TBDPS OH
O 9
8
O
d
O
O
O
TBDPS
O N
Br
e
O
Br O
O O
11
O
TBDPS N
g
O
12
O TBDPS
N
i
(R)
H
(R)
H OH
O
O
H O
O 13
O 14
15 j
j
j
HO
HO
HO
(R)
O
O
O
3
H
O
O O
O
O
(R)
H
H OH
H
N
(R)
(R)
(R)
k
N
N
N
O
O
N
h
(R)
O
O
O
10
TBDPS
O
(R)
f
Br O
N
O (-)-2
(-)-4
(-)-1
Scheme 1. Reagents and conditions: (a) TEA (1.5 equiv), Ac2O (5.4 equiv), 140 °C, 8 h, 73%; (b) H2SO4 (2 equiv), MeOH, 65 °C, 5 h, 70%; (c) TBDMSCl (1.2 equiv), imidazole (2 equiv), DMF, rt, 5 h, 86%; (d) (i) BF3Et2O (1.2 equiv), PIFA (1.1 equiv), CH2Cl2, 40 °C, 20 min, (ii) LiAlH4 (3 equiv), THF, 0 °C, 20 min, 73% (2 steps); (e) Br2 (1.05 equiv), CHCl3, 0 °C, 5 h, 30%; (f) 16 (1 equiv), TEA (2 equiv), CH3CN, rt, 3 h, 77%; (g) n-BuLi (2.2 equiv), THF, 78 °C, 4 h, 83%; (h) NaBH4, MeOH/THF 2/1, 0 °C to rt, 3 h, 66%; (i) Et3SiH (2.2 equiv), TFA, rt, 1 h30, 70%; (j) TBAF (1 equiv), THF, rt,
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl
Synthesis and biological evaluation of ( )-6-Odesmethylcryptopleurine and analogs Frédéric Liéby-Muller ⇑, Frédéric Marion, Philippe Schmitt, Jean-Philippe Annereau, Anna Kruczynski, Nicolas Guilbaud, Christian Bailly Institut de Recherche Pierre Fabre, CRDPF/CROE, 3 avenue Hubert Curien, BP 13562, 31035 Toulouse Cedex 1, France
a r t i c l e
i n f o
Article history: Received 29 September 2014 Revised 27 November 2014 Accepted 28 November 2014 Available online 6 December 2014 Keywords: Phenanthroquinolizidine alkaloid ( )-Cryptopleurine Cytotoxicity
a b s t r a c t ( )-Cryptopleurine 1 is one of the most potent anti-proliferative member of the phenanthroquinolizidine class of alkaloids. We report here the synthesis of ( )-6-O-desmethylcryptopleurine ( )-2 and ( )-6-Odesmethyl-(15R)-hydroxycryptopleurine ( )-4 in their enantiomerically enriched form through a convergent synthetic route, where the chirality is introduced by the use of commercially available (R)-methyl piperidine-2-carboxylate hydrochloride 17. Anti-proliferative activities of these compounds were evaluated on a panel of four cancer cell lines, revealing that compounds ( )-2 and ( )-4 are potent cytotoxic compared to cryptopleurine. Ó 2014 Elsevier Ltd. All rights reserved.
( )-Antofine A and ( )-cryptopleurine ( )-1 are plant metabolites belonging, respectively, to the phenanthroindolizidine and phenanthroquinolizidine class of alkaloids. Their isolation from various plant species,1 as well as their syntheses have been well described.2 These compounds are known to exhibit high anti-proliferative activities against several cancer cell lines, showing IC50 values in the low nanomolar range for cryptopleurine and around 10 8 M for antofine (Fig. 1). ( )-6-O-Desmethylantofine B, another closely related natural analog of antofine has gained attention more recently due to the significant improvement of activity provided by the sole loss of a methyl group.3 Based on this observation, we hypothesized that applying this specific substitution pattern by removing the 6-Omethyl of ( )-1 should lead to a more potent derivative.4 So, we wish to report here the total synthesis of ( )-6-O-desmethyl-cryptopleurine ( )-2 and its antiproliferative activities on a panel of four cancer cell lines. Both analogs 3 and ( )-4, obtained during the synthetic process, were also evaluated. The synthesis of compounds ( )-2 and ( )-4 is based on work previously reported by Wang et al.,2 and is depicted on Scheme 1. Condensation of commercially available aldehyde 5 and benzoic acid 6 afforded compound 7. Subsequent esterification with methanol in the presence of sulfuric acid led to 8. At this stage, we had to protect the phenol group. First attempts using a benzyl protecting group, as previously described,2b led, in our hands, to a poorly ⇑ Corresponding author. Tel.: +33 5 34 50 69 38; fax: +33 5 34 50 30 54. E-mail address: [email protected] (F. Liéby-Muller). http://dx.doi.org/10.1016/j.bmcl.2014.11.086 0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.
reproducible synthesis, notably due to the lack of solubility of the intermediates. The use of a tert-butyldiphenylsilyl ether (TBDPS) proved to be the better protection strategy to pursue a tractable
O
HO N (R)
Increase in potency
N (R)
H
H
O
O O
O
(-)-antofine A IC50 (A549) = 10 nM
(-)-6- O-desmethylantofine B IC50 (A549) = 1 nM
Increase in potency O
HO N (R)
N
Potency ?
(R)
H O
H O
O (-)-cryptopleurine (-)-1 IC50 (A549) = 1.9 nM
O (-)-6- O-desmethylcryptopleurine (-)-2
Figure 1. Chemical structures of A, B, ( )-1, ( )-2 and ( )-4.
185
F. Liéby-Muller et al. / Bioorg. Med. Chem. Lett. 25 (2015) 184–187
O
O
O
H
O
HO
O
HO
O
O
TBDPS
OH
O
O
a
b
O
c
O O
5
O
O
OH
O
6
7
TBDPS
TBDPS OH
O 9
8
O
d
O
O
O
TBDPS
O N
Br
e
O
Br O
O O
11
O
TBDPS N
g
O
12
O TBDPS
N
i
(R)
H
(R)
H OH
O
O
H O
O 13
O 14
15 j
j
j
HO
HO
HO
(R)
O
O
O
3
H
O
O O
O
O
(R)
H
H OH
H
N
(R)
(R)
(R)
k
N
N
N
O
O
N
h
(R)
O
O
O
10
TBDPS
O
(R)
f
Br O
N
O (-)-2
(-)-4
(-)-1
Scheme 1. Reagents and conditions: (a) TEA (1.5 equiv), Ac2O (5.4 equiv), 140 °C, 8 h, 73%; (b) H2SO4 (2 equiv), MeOH, 65 °C, 5 h, 70%; (c) TBDMSCl (1.2 equiv), imidazole (2 equiv), DMF, rt, 5 h, 86%; (d) (i) BF3Et2O (1.2 equiv), PIFA (1.1 equiv), CH2Cl2, 40 °C, 20 min, (ii) LiAlH4 (3 equiv), THF, 0 °C, 20 min, 73% (2 steps); (e) Br2 (1.05 equiv), CHCl3, 0 °C, 5 h, 30%; (f) 16 (1 equiv), TEA (2 equiv), CH3CN, rt, 3 h, 77%; (g) n-BuLi (2.2 equiv), THF, 78 °C, 4 h, 83%; (h) NaBH4, MeOH/THF 2/1, 0 °C to rt, 3 h, 66%; (i) Et3SiH (2.2 equiv), TFA, rt, 1 h30, 70%; (j) TBAF (1 equiv), THF, rt,
