Keto C-glycosides. a new class of antitumor compounds

Broorganic & Medicinal Chemslry Lakrs, Vol.1. No& pp. 395-398, 1991 Printed in Great Britain

0960-894X/91 $3 00 + .OO 0 1991 Pergamon Press plc

KETO C-GLYCOSIDES. A NEW CLASS OF ANTITUMOR COMPOUNDS. Jean Herscovici*s,

M. Idriss Bennani-Baittt,

Charles Frayssinett

ILaboratoire de Chimie Organique Biologique et Spectroscopique.

and Kostas Antonakisg.

Institut de Recherches Scientitiques

Sur le Cancer, CNRS, 94801 Villejuif, France. tLaboratoire

de Pathoiogie Ceilulaire. Institut de Recherches

Scientifiques

Sur le Cancer, CNRS,

94801 Villejuif, France.

(Received 30 May 199 1)

A series of 4-keto unsaturated

Abstract.

These compounds

against LFC12A cells (Rat hepatocarcinoma found cyctotoxic,

C-glycosides

and some parent 2-keto unsaturated whereas

l-methyl

was synthesized C-glycosides

cells). C-Glycosides

cyclohexenyl

from 0-acetyl C-glycosides.

were tested for cytotoxic

activity

with an acyclic aglycone have not been

and methylene

cyclohexenyl

C-glycosides

possessed

ICso values of 9-0.03 FM with 11 being the most potent Screening

of plant extracts has led to the isolation of a large number of sesquiterpene

derivatives

having cytotoxic properties1v2. The activity of these compounds derives from the presence of a C=C-C=O system such as a-methylene as alkylating recognized

y-lactones,

agents by a Michael

that the usefulness

high toxicitys.

Investigation

ap-unsaturated

addition

ketones, lactones, esters or epoxides3 whtch act

with biological

of most natural sesquiterpene

nucleophilest.2.4.

However

it is widely

lactones has been limited by their relatively

to reduce toxicity has resulted in synthetic

modification

of amethylene

lactones and preparation and testmg of synthetic anaIogue&-lo. One rational of designing

less toxic drugs is to introduce

an alkylating

biologically

active molecules.

nucleosides

exhibited cytotoxic properties 11 and inhibited tumor growth in vivo12.

Recently polyfunctional

Thus our group has previously

we have reported

aglycone by the condensation

antitumor activity demonstrated further synthesize available

to prepared

C-glycosides.

2,3 unsaturated

C-glycosides

keto

with a

glyca113-ts. The significant

and related derivatives encouraged

us to

Because of the wide range of structures

to assume that these molecules

the structure activity relationships

to other classes of

that keto or unsaturated

of an olefin with a peracetylated

by keto unsaturated nucleosides

and evaluate keto unsaturated

it would be reasonable

understanding

new methodologies

reported

group

could be valuable tools for a better

in order to design antitumor agents acting with a better

selectivity. To explore the effect of the aglycone on cytotoxic activity, 4-keto unsaturated with a linear aglycone and enones lo-14 with a l-methyl

cyclohexene

C-glycosides

or a methylene

8 and 9

cyclohexene

unit

bond to the anomeric carbon, were prepared. The synthesis was carried out in two steps (scheme 1) from the previously reported acetates 1-7 prepared by methods developed in our laboratory13-l5 Deacetylation

395

J. HERSCOVICIer al.

396

AcO+

CHO

CHO

b 150

a

OAc Cl

4323 w 16 0

11

crb '0

0

14

-

a MeONa MeOH RT b PDC 4A MS or Mn02 scheme

1

Keto C-glycosides

using sodium However

methoxide

then oxidation

under these conditions

with PDC/4A

397

MS16 afforded

the D-gluco derivative

the enone in 60-80%

yield

12 was isolated in 20% only. Treatment

of 12

with 10 equivalents of MnO2 gave the P-keto alcohol 12 in 50 % yield. The cytotoxicity

of the unsaturated

keto C-glycosides

was determined

established

cell line derived from an hepatocarcinoma

azobenzene

(DAB)t7-19. In addition some 2-keto unsaturated C-glycosides14

against LFCl2A

induced in the Commentry

cells, an

rat by dimethylamino

were also evaluated. All the

result was summarized in Table 1. Table

1 in vitro cytotoxicity

Compounds 7

40

8

60

9

80

10

3

11

3 x 10-Z

12

7

13

9 x 10-Z

14

9

15

40

16

3x10-’

17

3

5fluoro uracil

Examination

IC5o (PM)

28.5

of the data deserves further comments.

showed no activity. On the other hand C-glycosides IC50 values ranging

C-glycosides

8,9 and 15 with a linear aglycone

lo-14 and 16-17 were found to be cyctotoxic

from 9 to 0.03 pM. As expected

the antitumor

activity

was dependant

with on the

presence of the keto group as evidenced by the results recorded for acetate 7. In addition Table 1 revealed clearly the importance or pentahexopyranosyl glycosides compounds.

ll(IC50

C-glycosides

were moderately

of the substitution cytotoxic

at C-5. Thus, 5-hydoxymethyl

whereas 6-deoxy keto unsaturated

C-

0.03 PM), 14 (IC50 0.09 FM) and 16 (IC50 0.3 l.rM) were the most active

Finally the 4-keto derivatives

seemed to be slightly more cytotoxic

than the 2-keto C-

glycosides. Acknowledgement.

We gratefully

acknowledge

Recherche sur le Cancer” (ARC), Villejuif, France.

the financial

support of the “Association

pour la

398

J. HERSCOVICIet al.

References

and Notes.

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19 LFCllA

cells were grown in EMEM (Eagle’sMinimal

Essential

Medium, Eurobio)

supplemented

with 10% NCS (New born calf serum, 6 Flow Laboratories) , 2 mM glutamme and antibiotics UI penicillm/ml

and 100 pg streptomycin/ml).

(100

They were usually seeded at 25,000 cells/ml medium

in culture flask incubated at 37°C in a humidified incubator with an atmosphere of air/CO2 of95/5 and subcultured twice a week. Cell suspensions dilutions

of keto-C-glycosides

added to wells of microplates cytotoxics

(2(X) ~1) were dispensed in wells of microtest plates. The

to be tested were performed together

in DMSO, 1 pL of &h

with the cells suspensions.

for 72 hours. Twelve hours before the cells were harvested,

added to each well. Cultures

were washed

(Skatron) on glass fiber filters (Whatmann).

and collected

dilution was

Cells were Incubated with the 1 FCi tritlated thymidine was

with an automated

sample

The filters were dried and the radlonctivlty

harvester

was counted

in omnifluor in a liquid scintillation spectrometer. Each experiment was conducted in tripllcnte.