B~ochemi~lPharmacology,Vol.26. pp.2469-2472.PergamonPress,l977.

THE SYNTHESIS

AND ANTITUMOR

John A. Beisler, Drug Design

and Chemistry

i’mted

ACTIVITY

Mohamed

NCI, NIH, Bethesda,

(Received

The antitumor prompted

and antiviral

us to initiate

The arabinosyl

arabinofuranosyl-5-azacytosine

triazine

ring with respect

of ara-AC

difficulty

to reduction

for the synthesis as a synthetic

derivative

Materials

attractive

elements

as a synthetic (5-AC) which

and btethods.

indicate

thermal

to the conversion an earlier,

reactions.

reaction

attempt

(6).

This intermediate

synthesis

which

is shown in Scheme

of the 5,6-double

starting

to give

to 5-AC

(5).

ara-AC, (I) was

material

of I in ethanolic

bond in the triazine

derivative

of a per-trimethyl-

to synthesize

described

led to the reduction

of the

5,6-dihydro-

of the dihydro

of dihydro-5-azacytidine

Hydrogenation

The

AC

Because

of 1-(2,3,5-tri-0-benzyl-8_D-arabinofuranosyl)-5-azacytosine

1.

1-B-g-

step, dehydrogenation

elimination

an appropriate

is used

structure

the preparation

seemed

goal because

than 5-AC (2), a reasonable

utilization

unsuccessful

of ara-C.

lies in the instability

In a final synthetic

via the novel -

In

attack

(ara-C)

of both ara-C and 5-AC.

of ara-AC

to nucleophilic

of ara-AC would

analogous

1977)

,A!

and nucleophilic

intermediate.

and Biology,

the 5-aza bioisostere

In terms of chemical

in the preparation

is much more stable

ara-AC might be accomplished silylated

13 September

‘1 AC

synthetic

5-azacytidine

Chemistry

20014

to 5-azacytidine

contains

c

inherent

strategy

(4).

(ara-AC)

Maryland

to prepare

related

of leukemia

of Medicinal

(1) of l-B-Q-arabinofuranosylcytosine

was additionally

(2,3) in nucleosides

and John S. Driscoll

1977; accepted

effort

a synthetic

in the treatment

ard

activity

5-aza derivative

of our interest clinically

7 September

Britam

OF ARABINOSYL-5-AZACYTOSINE

M. Abbasi

Laboratory

Section,

mGreat

for the present

hydrogen

chloride

ring as well as effecting

the

7470

Commumcations

Prelminaty

hydrogenolysis

of

the

syl-5-azacytosine H20);

benzyl

hydrochloride

NMR (Me2SO-d6)

Scheme

protecting

groups

(II)

6 5.77

in

(doublet,

J = 5Hz,

(BSTFA)

in

shown

hours

of

by

of

room

solution gas

the

which

temperature

dec., C-6

due

lH,

CI,H),

dec.;

4.70

[ tjz4_ -2h” cc I

(broad

singlrt,

2H,

0 ,

i’6il).

was

24

[c11

to

the

spectrum

with

the

5-AC,

1.0, of

C-6

reduced

was

methanol

as

The

of

5-AC

nucleoside

replaced

by

to

remove

= 4Hz).

In

in

the

solvent

the

(II),

a singlet

III

(J

at

same

the

3s

thr

>olut

in

by

82”

virld:

Lle2SO-d6

RS 11 chars>

appear-cd

aromatic,

soIuti~)n

rre:;ponding

(.I,

s inglvt

Ln LllC

H.hO.

~./I~~T~I< trriitic

single,t,

nttributablk.

ion

mp 22?-

singlc,t

thE

iI

tetrakis-

reaction

in

comparison,

low-field

II 4.70

III

oi

Af 1er j 3

.

trimethylsilyl~roups

,i 8.22

at

*

analvsis

solution

of

deriv,ltivc

to of

the froix

nucleus

a doublet

proton

Evaporation

NMR spectrum

triazine

(GC-hfS)

conversicrn

crystallized

H20). the

CC-MS.

Inrlro:icetnmide

~)entakis-trimethylsii~,l

spectrometry

by

(III)

6 6.03

aromatic

of

and

at

the

a complete

evident

boiled

proton

proton

gave

solution,

was

D L22”(c

aromatic

_bis-(trimethylsilyl)-trif

chromatography-mass

silylation

III

with

readily

Arabinosyl-5-azacytosine

anomeric

III

at

derivative

a syrup

lysis.

II

combined

trimethylsilyl

the

mp 166-169”

II

acetonitrile

reflux

225”

5,6-dihydro-l-d-I)-arat,in(~fu~-~lno--

I

Treatment

gave

provide

79% yield:

I

as

to

pair

,li

i-f>

101

;:wthvii-ne,

protons.

The later

the

respective 241

UV spectrum maximum values

nm (E 6,800)

(7,s)

by

larger

a facile

extinction

derivative

*

(III)

of

III

shifted

to

recorded and

241

water

242

for

coefficient

5-AC

very

The GC-PIS system and other instrumentation

reaction at similar

solution

nm and

nm (E 7,700)

hydrolysis

has

in

at

the the

showed

a maximum