Biphenyls as surrogates of the steroidal backbone. Part 2: discovery of a novel family of non-steroidal 5-alpha-reductase inhibitors.

A new family of non-steroidal 5-alpha-reductase inhibitors was designed by replacing the steroid skeleton of an inhibitor related to estrone by a biphenyl moiety. This hypothesis originated from the reported estrogenic activity of a few biphenyl compounds (see Part 1 of this paper; Lesuisse et al. Bioorg. Med. Chem. Lett. 2001, 11, 1709). Two compounds turned out to be potent type 2 5-alpha-reductase inhibitors with IC(50)'s of inhibition in the nanomolar range. These are to our knowledge amongst the most potent non-steroidal 5-alpha-reductase inhibitors described to date.

RGD mimetics containing a central hydantoin scaffold: alpkha(v)beta3 vs alpha(IIb)beta3 selectivity requirements.

The synthesis of a series of RGD mimetic alpha(v)beta3 antagonists containing a hydantoin scaffold is shown. The results demonstrate some of the structural requirements for the design of selective alpha(v)beta3 antagonists (vs alpha(IIb)beta3) in terms of the Arg-mimetic, the distance between N- and C-terminus and the lipophilic side chain.

Determination of oenothein B as the active 5-alpha-reductase-inhibiting principle of the folk medicine Epilobium parviflorum.

Several extracts from Epilobium parviflorum, a plant used in Central Europe for the treatment of prostate disorders, were evaluated in a biochemical assay with 5-alpha-reductase. The aqueous extract displaying inhibition of the enzyme was analyzed, the fraction responsible for this activity was purified, and the active compound identified as a macrocyclic tannin, oenothein B (1).

Structure-activity relationships of a new family of steroidal aromatase inhibitors. 1. Synthesis and evaluation of a series of analogs related to 19-[(methylthio)methyl]androstenedione (RU54115).

During the course of a study aimed at the search for new potent aromatase inhibitors, several new androstenedione analogs were synthesized and evaluated. This study led to the discovery of 19-[(methylthio)methyl]androsta-4,9(11)-diene-3,17-dione (7; RU54115) already described by our laboratory. The object of the present series of papers is to disclose the result of the structure-activity relationship studies that gave rise to this compound. This first part deals mainly with the substitution in the 19-position of the steroid nucleus. Several parameters were varied, the length of the chain and its rigidity and branching, as well as the nature of the heteroatom itself and its substitution. The interaction of these new compounds with human placental aromatase in competition with the substrate androstenedione was studied by difference visible spectroscopy. The in vivo aromatase-inhibiting activities were evaluated by measuring the estradiol lowering after oral administration of the compounds to PMSG-primed female rats.

Partial prevention of glutathione depletion in rats following acute intoxication with diethylmaleate.

To assess the ability of L-2-oxothiazolidine-4-carboxylate (OTC) to stimulate the biosynthesis of glutathione (GSH) in non-fasted male rats, the time-courses of GSH and cysteine contents were studied in liver, kidney, heart and brain, following a single intraperitoneal injection of OTC (5 mmol/kg), with or without co-administration of the GSH depletor diethylmaleate (3 mmol/kg). In the absence of diethylmaleate, OTC did not change the GSH or cysteine content of heart and kidney. The liver was the only organ where systemic administration of OTC resulted in a fast and quasi-linear increase in GSH as a function of time, with no appreciable lag-time. A maximal, i.e. 2.1-fold increase in liver GSH was induced by OTC at the times corresponding to the low GSH values of the diurnal cycle observed in control rats. A smaller, i.e. 1.4-fold increase in brain GSH was observed after 6 hours. A marked increase in cysteine always preceded that of GSH in liver and brain. In the liver, the OTC-mediated stimulation of GSH biosynthesis was optimal when cysteine delivery was achieved at the onset of the cysteine decrease that was observed in the diurnal cycle of control rats. These results support the view that cysteine is a limiting factor in the biosynthesis of GSH. Following an acute dose of diethylmaleate (3 mmol/kg), OTC afforded a general and significant protection of rat tissues against GSH depletion.(ABSTRACT TRUNCATED AT 250 WORDS)

Synthesis and evaluation of a new series of mechanism-based aromatase inhibitors.

A series of new 4-(alkylthio)-substituted androstenedione analogues was designed as potential suicide inhibitors of aromatase on the basis of mechanistic considerations on the mode of action of the enzyme. Their synthesis and biological evaluation are described. Among the most interesting are the 4-[(difluoromethyl)thio]-, 4-[(fluoromethyl)thio]-, and 4-[(chloromethyl)thio]androstenediones 12, 13, and 14 with respective IC50's of 2.7, 0.8, and 0.94 microM. Compound 12 was a reversible inhibitor of aromatase while compounds 13 and 14 displayed time-dependent kinetics of inhibition with respective KI's and half-times of inactivation of 30 nM and 3.75 min for 13 and 30 nM and 3 min for 14. The inhibition of aromatase by 14 was NADPH-dependent, and was protected by the presence of substrate (0.5-1 microM), while beta-mercaptoethanol (0.5 mM) failed to protect the enzyme from inactivation. Dialysis failed to reactivate aromatase previously inactivated by 14. The mechanistic implications of these findings are discussed.

RU54115, a tight-binding aromatase inhibitor potentially useful for the treatment of breast cancer.

RU54115 is a new potent inhibitor of aromatase. In vitro, it inhibits the enzyme from human placental microsomes with a Ki of 0.5 nM, which places it among the tightest reported steroidal inhibitors of aromatase. In vivo, it lowers the amount of circulating estradiol in pregnant mare serum gonadotrophin (PMSG)-primed female rats with an ED50 of 0.4 mg/kg when given s.c. and 4 mg/kg when given orally. An oral dose of 25 mg/kg when given once daily to female rats was able to inhibit the growth of DMBA-induced mammary tumors.