Current Medicinal Chemistry, 2005, 12, 927-943 927 Recent Advances in the Chemistry and Pharmacological Activity of New Steroidal Antiandrogens and 5 -Reductase Inhibitors Eugene Bratoeff *,2 , Marisa Cabeza 1 , Elena Ramirez 2 , Yvonne Heuze 1 and Eugenio Flores 2 1 Department of Biological Systems and Animal Production, Metropolitan University-Xochimilco, Mexico D.F.,Mexico. 2 Department of Pharmacy, National University of Mexico City, 04510 Mexico D.F.,Mexico Abstract: The object of this paper is to summarize for the past two years the most recent development in the field of prostate cancer and 5α-reductase inhibitors. In addition we are also including some results on the synthesis and pharmacological evaluation of new steroidal compounds developed in our laboratory. Most of the new steroidal derivatives are based on the progesterone skeleton and showed a high inhibitory activity for the enzyme 5α-reductase. Presently, similar compounds are used for the treatment of androgen dependent diseases such as: hirsutism, androgenic alopecia, benign prostatic hyperplasia and prostate cancer. Dihydrotestosterone 2 (Fig. 1) a 5α-reduced metabolite of testosterone 1 has been implicated as a causative factor for the progression of these diseases, largely through the clinical evaluation of males who are genetically deficient of the enzyme steroid 5α-reductase. As a result of this study, the inhibition of this enzyme has become a pharmacological strategy for the design and synthesis of new antiandrogenic drugs. The advent of finasteride 7 (Fig. 3) a 5α-reductase inhibitor has greatly alleviated the symptoms associated with benign prostatic hyperplasia. In our laboratory, we recently synthesized several new 16β-methylpregnadiene-3,20-diones: 40 , 41 (Fig. 8), 16 β-phenylpregnadiene-3,17a-dione derivatives 46 and 47 (Fig. 9) and 49 (C-4 bromoderivative) (Fig. 11 ), 52 - 56 (Fig. 13 ). The analogue pregnatriene derivatives were also prepared: 44 , 45 (Fig. 9) 50 , 51 (Fig. 11) and 57- 60 (Fig. 13 ) These compounds were evaluated as 5α-reductase inhibitors in the following biological models: Penicillium crustosum broths, the flank organs of gonadectomized male hamsters, the incorporation of radiolabeled sodium acetate into lipids, the effect of the new steroids on the reduction of the weight of the seminal vesicles and on the in vitro metabolism of [ 3 H]T to [ 3 H]DHT in seminal vesicles of homogenates of gonadectomized male hamsters. All trienones 44 , 45 , 50 , 51 and 57 -60 in all biological models showed consistently a higher 5α-reductase inhibitory activity than the corresponding dienones: 40 , 41 , 46 , 47 , 49 and 52 -56 . We believe that with these compounds the 5α-reductase enzyme is inactivated by an irreversible Michael type addition of the nucleophilic portion of the enzyme to the conjugated double bond of the steroid. The trienones having a more coplanar structure react faster with the enzyme thus showing a higher inhibitory activity. INTRODUCTION 3α -hydroxysteroid dehydrogenase and the 17β- hydroxysteroid dehydrogenase [4]. The mechanism of action of steroidal hormones begins when they migrate from the blood stream to the cell across the cell membrane by a simple diffusion mechanism. Once inside the cell, the steroids form complexes with intracellular binding proteins called receptors which are specific protein tissues. Steroid receptors were discovered in 1968 [1], changing the concept of the mechanism of action of steroid hormones in those days. Latter Metcalf [2] demonstrated that hormone-receptor binding, triggers a cascade of events that permits the expression of specific genes. The 17β-hydroxysteroid dehydrogenase has the capacity to convert testosterone to androstenedione and this compound is converted to 5α -androstanedione by the action of 5α -reductase. The 5α -androstanedione is transformed to androstanediol by the action of 3α -hydroxysteroid dehydrogenase enzyme [4-6]. Presently there are several compounds available that can inhibit the mechanism of action of steroid hormones. These inhibitions are carried out at different levels such as: 1) blocking the receptors using an antagonist, 2) inhibiting metabolic enzymes involved in steroidgenesis by chemical agents, 3) inhibiting the mechanism of activation of receptors on molecules that interact with chaperon or Fos and Jun proteins, 4) inhibiting the phosphorylation changes in receptor molecules and 5) modifying the hypothalamic pituitary axis. Inside the cells, the uptaken steroidal hormones undergo modifications in its molecule producing active metabolites that trigger a cascade of reactions. These molecular changes are due to the presence of enzyme specific tissues. In the prostate, for example, the 5α -reductase enzyme type 2 [3] catalyzes the conversion of testosterone 1 (T) to 5α - dihydrotestosterone 2 (DHT), (Fig. 1). This metabolite is responsible for the induction of some enzymes such as the Reports in the literature describe a variety of natural or synthetic steroids having antiandrogenic action. Cesorsimo in 1970 [7] demonstrated that progesterone 3 and deoxycorticosterone 4 inhibit the DHT formation by competing with ∆ 4 -3-keto site on the testosterone molecule *Address correspondence to this author at the Facultad de Quimica- UNAM, Ciudad Universitaria, 04510 Mexico D.F., México; E-mail: eugene@servidor.unam.mx 0929-8673/05 $50.00+.00 © 2005 Bentham Science Publishers Ltd.