Suprabhat Ray

Seco-oestradiols and some non-steroidal oestrogens: structural correlates of oestrogenic action.

Abstract Oestrogens can be grouped into two classes, based on their structural characteristics and biological activities; the typical oestrogens exemplified by the steroidal and the stilbene types, and the atypical oestrogens by the triaryl-ethylene types. In order to gain an understanding into the relationship between molecular structure and biological activity of oestrogens, receptor affinity, uterotrophic and antiimplantation activities of various 5,6-seco- and 9,11-seco-oestradiols, representing flexible analogues of the parent prototype, and certain 3-phenyl-4-aryl-chromenes and -chromans, representing triaryl-ethylene and -ethane prototypes incorporated into a rigid framework, have been studied. Comparative receptor affinity and biological activity of the seco-oestradiol analogues revealed the importance of the features of planarity and molecular rigidity of oestradiol-17β for its high affinity to the receptor, and also led to a better appreciation of the characteristics of the receptor regions involved in binding around C-3, C-8, C-9 and C-18 of oestradiol. The results of the study on chromenes and chromans indicated that in triaryl-ethylene oestrogens, t-aminoalkoxy-phenyl residue plays an important role in receptor binding and biological activity. A study of the influence of alkyl groups at C-2 of the chromene and chroman analogues revealed noteworthy information about the general stereochemical requirements of these molecules for an optimum receptor fit. A consideration of these results and the findings previously reported in literature point to the possibility that all the molecular types considered here, interact with a common binding site of the receptor, albeit in a different stereochemical fashion, which may be one of the reasons for the differences in their biological activities.

Comparative antimutagenic effects of D- and L-centchroman and their comparison with tamoxifen in Salmonella assay.

Centchroman (CC)--a contraceptive and a candidate drug for breast cancer has been developed by the Central Drug Research Institute. It has been successfully marketed as a contraceptive for last several years. CC has also been reported to exhibit partial to complete remission of lesions in 40.5% breast cancer patients. Recently, we have reported the antimutagenic effects of CC in Ames Salmonella assay and in vivo and in vitro mammalian cells in multiple mutational assay. The potent antimutagenic activity of CC and its anti-breast cancer activity prompted us to evaluate the antimutagenic effects of its enantiomers, i.e., D-centchroman (DC) and L-centchroman (LC) in the Ames Salmonella strains TA97a, TA98, TA100 and TA102 against known bacterial mutagens. Attempts have also been made to compare the results of antimutagenicity assays of CC and its enantiomers with the known breast cancer drug tamoxifen (TM). The main objective was to identify the best suitable form of CC having antimutagenic effects with anticancer profile similar to TM, would replace the latter for toxicity reasons. When mutagenicity assays were carried out with these compounds as expected like CC, none of these enantiomers or TM showed any mutagenic effects in these Salmonella strains. In the antimutagenicity assay a significantly reduced number of bacterial histidine revertant colonies were observed when positive compounds were co-incubated with certain concentrations of LC compared with bacterial plates treated with respective positive compound. This was observed in some concentrations in all the four strains in both plate incorporation and preincubation tests. The protective effects of LC in preincubation tests were slightly more than in plate incorporation tests. Both the DC and TM showed protective effects only in certain concentrations in some strains in either plate or preincubation tests. Thus the above results indicate that LC showed more protective effects in Salmonella strains TA97a, TA98, TA100 and TA102 than either DC or TM.

AN EFFICIENT ONE POT SYNTHESIS OF CARBAMATE ESTERS THROUGH ALCOHOLIC TOSYLATES

ABSTRACT An efficient O-alkylation of alcoholic tosylates with amines in a K2CO3/CO2 system in the presence of tetrabutyl ammonium iodide (TBAI) provides exclusive formation of carbamates. *CDRI-Communication no: 6143.

Enhanced antifertility activity of non-steroidal molecules with 3- n -butylamino-2-hydroxypropyloxy side chain

A comparative study of relative binding affinity (RBA) for estradiol-17 beta-receptors, estrogenicity and antifertility activity of compounds 2,2-dimethyl-3-phenyl-4-p-(3-n-butylamino-2-hydroxypropyloxy-pheny l)- 7-methoxycoumarin 4, 2,2-dimethyl-3-phenyl-4-p-(3-n-butylamino-2-hydroxy-propyloxyphenyl++ +)-7-methoxy chromene 5 and trans-2,2-dimethyl-3-phenyl-4-p-(3-n-butylamino-2-hydroxypropyloxyphe nyl)- 7-methoxychroman 6 with the corresponding 4-p-(beta-pyrrolidinoethoxyphenyl) compounds 1-3, is reported. It has been found that the introduction of the novel 3-n-butylamino-2-hydroxypropyloxy moiety in place of the classical tert-beta-aminoethoxy group leads to enhancement of antifertility activity.

An efficient, basic resin mediated, one-pot synthesis of dithiocarbamate esters through alcoholic tosylates

A novel process for the one-step conversion of alcoholic tosylates into dithiocarbamates as protected amines was developed using basic resin (amberlyte IRA 400) in presence of carbon disulfide. Dithiocarbamates of different amines were isolated in very good to excellent yields. This protocol is mild, chemoselective and efficient compared to other existing methods.

A Novel Synthesis of Bisbenzyl Ketones by DCC Induced Condensation of Phenylacetic Acid

Abstract 1,3-Dicyclohexylcarbodiimide (DCC) has been found to effect condensation of two molecules of phenylacetic acids in the presence of dimethylaminopyridine leading to the formation of bisbenzyl ketones. CDRI communication No. 5670

An efficient, basic resin mediated, one-pot synthesis of O-alkyl-S-methyl dithiocarbonates from the corresponding alcohols

A novel process for the one-step conversion of primary and secondary alcohols into their O-alkyl-S-methyl dithiocarbonates was developed using Amberlite IRA 400 (basic resin) in presence of carbon disulfide. O-Alkyl-S-methyl dithiocarbonates of various alcohols were isolated in very good to excellent yields. This protocol is mild and efficient compared to other existing methods.

CONVENIENT AND SELECTIVE ACETYLATIONS OF PHENOLS, AMINES AND ALCOHOLS

Two convenient methods have been developed for selective acetylation. In method 1, phenols and amines are selectively acetylated in the presence of alcohols by acetic anhydride in a biphasic aqueou...

Synthesis of novel 6-aza-B- and 11-aza-C-homoestranes as antifertility agents ☆

Reaction of 3,9 alpha, 17 beta-trihydroxyestra-1,3,5(10)-trien-11-one 17-acetate 3-methyl ether (3) with N3H-BF3 etherate leads mainly to lactam (4) along with the N-azido compound (5) as a minor product. Under similar conditions, 3,17 beta-dihydroxyestra-1,3,5(10)-trien-6-one 17-acetate 3-methyl ether gives lactam (12) and the tetrazole derivative (9). Similar reaction of the diacetate (8) gives only the tetrazole derivative (11). Compounds 4, 6, and 10 prevent implantation in rats at 5-, 10-, and 5-mg/kg doses, respectively. Compounds 4, 6, 9, and 10 show significant estrogenic activity at the respective contraceptive doses.

Effect of centchroman on the uptake of tritiated estradiol-17β and progesterone by different tissues of ovariectomized rats

Abstract The effects of centchroman on the uptake of 6,7- 3 H-estradiol and 1,2,6,7- 3 H-progesterone by different tissues in ovariectomized young adult rats were studied. Pre-treatment with centchroman inhibited the uptake of radioactive estradiol by the hypothalamus pituitary, uterus, fallopian tube, adrenal and liver, but not that by plasma. In the other set of experimental animals, centchroman also counteracted the estradiol benzoate-induced increase in the weight of the pituitary, uterus and vagina, although administration of centchroman alone increased the weight of the pituitary and uterus in ovariectomized rats. These results may be explained on the basis of competitive inhibition of estrogen at target tissue level. Compared to the control group, the uptake of radioactivity as pure progesterone was more in all the tissues except the vagina and liver of the animals pre-treated with centchroman, whereas the uptake of total radioactivity was increased in the liver and plasma but remained unchanged in other tissues. The results indicate that centchroman, which has been claimed to have an anti-progestational action, did not accelerate the metabolism or elimination of progesterone, nor did it interfere with the uptake of progesterone by the target tissue.