Design and action of steroidal aromatase inhibitors

Abstract

The biosynthesis of estrogens involves three sequential hydroxylations, progressing from cholesterol, that are mediated by an enzyme complex referred to as aromatase. The last steps in this sequence involve aromatization of the A ring of the steroid nucleus. Compounds that inhibit aromatase have potential applications in the treatment of advanced estrogen‐dependent mammary carcinoma and prostatic hyperplasia. The enzyme aromatase is currently a priority target for the development of active‐site directed inhibitors. A number of steroid inhibitors may inactivate aromatase by diverse interactions with the enzyme and include competitive inhibitors, affinity labelling agents, and mechanism‐based inhibitors (“suicide substrates”). By designing steroidal analogs with substituents at various positions on the steroid nucleus, information has been obtained on the structural requirements needed for favorable interactions with the enzymatic sites.

Design and synthesis of new steroidal inhibitors of estrogen synthase (aromatase)

“…Derivatives with 6-fluoro, chloro, hydroxy, or acetoxy groups showed good activity in the inhibition of human placental aromatase in vitro (22,23). In these proposed mechanisms, the nucleophile (Enz-X) shown in Schemes 2 and 3 is from the sulfhydryl group on the amino acid cysteine found in the active site of the enzyme (5,24,25).…”

“…The heteroatom at C-19 could coordinate to the heme iron as the sixth ligand and compete with oxygen binding. Several of these types of inhibitors are modified as mechanism-based inhibitors, presumably undergoing enzyme-mediated oxidation at the C-19 carbon to form the alkylating group and in the process become potent enzymeactivated inhibitors of aromatase (4,5).…”

“…Consequently, regulation of estrogen biosynthesis has advanced as a potential therapeutic strategy (3,4). This has led to the development of active-site inhibitors that may have potential for the control of breast cancer (5).…”

“…It has been shown that three molecular oxygens and six reducing equivalents from NADH are consumed during estrogen formation. The mechanisms involved in this enzymatic process have recently been extensively reviewed (4,5).…”

3β,11α-Dihydroxy-17a-oxa-D-homoandrost-5-en-17-one

“…For background information on steroidal lactones and their properties, see: Braunstein (1999); Brodie & Njar (1998); Bydal et al (2009); Feuillan et al (1999); Li & Parish (1996); Dunkel (2006); Penov Gaši et al (2001Gaši et al ( , 2005. For the general method of preparation of the title compound, see: Kołek et al (2008).…”