Synthesis and Biological Evaluation of 16E-Arylidenosteroids as Cytotoxic and Anti-aromatase Agents

Abstract

Regular ArticleNew targets are being focused by medical chemist with the aim to provide new specific and potent drugs for the treatment of cancer. Mammary tumors represent the most widespread type of malignant neoplasm and most common cause of cancer in women between the ages of 30-54 1) and is the second leading cause of cancer deaths in women today (after lung cancer). About half of these malignancies require a source of estrogens for their growth and development. Estrogens are biosynthesized from androgens by the microsomal cytochrome P-450 enzyme system termed aromatase.2,3) Inhibition of aromatase is an important approach to reducing growth stimulatory effects of estrogens in estrogen-dependent breast cancer. 4) Effective aromatase inhibitors have been developed as therapeutic agents for controlling estrogen-dependent breast cancer. Aromatase inhibitors (AIs) can reduce estrogen production by more than 90% and in addition AIs lack estrogen-agonist activity unlike tamoxifen, the most widely used antiestrogen for the management of breast cancer.5) Recent clinical data have also shown that these inhibitors have greater efficacy than tamoxifen in late-stage disease and preliminary data indicate that this efficacy extends to early disease. Aromatase inhibitors therefore almost certainly replace tamoxifen as the hormonal agents of choice for the treatment of breast cancer. 5,6) Despite the success of the third-generation steroidal and nonsteroidal AIs, they still have some major side effects, such as the increase of bone loss. For this reason, it is important to search for other potent and specific molecules with lower side effects. Taking into consideration the significance of azole groupings of many specific and potent P450 inhibitors including aromatase, 7) we have introduced imidazole group in androstane nucleus in the present study.A large number of potent steroidal derivatives with substitution at position 16 have been described in the literature as potent cytotoxic agents.8-10) Recent work from our laboratory has also demonstrated the effectiveness of 16E-arylidenosteroids as potential antitumour agents.11-13) These observations prompted us to prepare and study some more new 16E-arylidenosteroids possessing an imidazole group to obtain dual cytotoxic as well as aromatase inhibitory effects. Results and DiscussionThe synthetic routes to the preparation of various new steroidal derivatives have been outlined in Charts 1-3. Base catalyzed aldol condensation of dehydroepiandrosterone (DHA) with 4-(3-chloropropoxy)-3-methoxybenzaldehyde Sector-14, Panjab University; Chandigarh-160014, India: and b Pharmaceutical and Medicinal Chemistry, Saarland University; D-66041, Saarbrücken, Germany. Received September 2, 2010; accepted December 27, 2010; published online January 5, 2011 Taking into consideration the structural requirements for cytotoxicity and aromatase inhibition, several new 16E-arylidenosteroidal derivatives have been prepared and evaluated for their cytotoxic and aromatase inhibitory activity. Th...

Synthesis and aromatase inhibitory activity of some new 16E-arylidenosteroids

“…Recent work from our laboratory has also demonstrated the effectiveness of 16E-arylidenosteroids as potential cytotoxic and aromatase inhibitors [13,14]. These observations prompted us to prepare and study some more new 16E-arylidenosteroids as aromatase inhibitors, in which structural features of various nonsteroidal aromatase inhibitors have been incorporated.…”

Exploration of new 3α-pregnenolone ester analogues via Mitsunobu reaction, their anti-HIV activity and molecular modeling study

“…Furthermore, different steroidal derivatives have been considered as potent anti-cancer agents for the treatment of leukemia [7], breast cancer [13][14][15], prostate cancer [16] and brain tumors [17]. Furthermore, some steroids are promising pharmaceutical targets for important indications like epilepsy, anxiety disorders and dementia [18], while other steroid hormones have long been recognized to have sedative, anesthetic and anti-seizure properties in animals and humans [19][20][21][22].…”

Recent developments in steroidal and nonsteroidal aromatase inhibitors for the chemoprevention of estrogen-dependent breast cancer

“…The imidazolyl-substituted steroidal derivatives exhibited good inhibitory activity against aromatase and 16-[4-{3-(imidazol-1-yl)propoxy}-3-methoxybenzylidene]-5-androstene-3β,17β-diol (11) (Fig.2.) had13 times more activity (IC 50 = 2.4 µM) than aminoglutethimide. [29] Next, a new series of 16E-arylidene derivatives were synthesized by introducing various aryl substituents at the 16 position of the steroid skeleton and its impact on aromatase inhibition was studied. Among these compounds, 3-keto-4-ene steroid (12) (Fig.2.…”

“…), a potent AI, led to the design and development of nonsteroidal AIs for the treatment of estrogen-dependent breast cancer. [42][43] The most potent nonsteroidal inhibitors, i.e., those with a high affinity for the enzyme, are the azole derivatives fadrozole (28), liarozole (29) with an imidazole ring, letrozole (30), anastrozole (31), and vorozole (32), all containing a 1,2,4 triazole ring (Fig.4.). Anastrozole and letrozole are very potent and selective AIs and are well tolerated by patients.…”

“…Compound 38 was a potent inhibitor of aromatase (IC 50 = 0.50 µM) and it was selective with respect to other steroidogenic P450 enzymes, i.e., CYP17 and CYP11A1. [58] M A N U S C R I P T (29) analogues based on an indole nucleus bearing the azolylbenzyl fragment at different positions of the aromatic bicycle. Several modifications were introduced, i.e., N-substituent, azole ring, and phenyl substituents; the most effective compounds were 39 (IC 50 = 0.10 µM) and 40 (IC 50 = 0.04 µM) (Fig.6.).…”