Synthesis and investigation of the biological properties of 6-oxa-8α-analogs of steroid estrogens containing a methyl group at C-4

Abstract

4-Methyl-substituted 6-oxa-8α-analogs of steroid estrogens have been synthesized and the 1 H and 13 C NMR signals of these compounds have been completely assigned. It is shown that introduction of a methyl group in position 4 of steroids of the given stereochemical series leads to the loss of uterotropic and hypertriglyceridemic effects of the modified compounds. Steroids with these properties may have promise for the creation of vectors for transport into target organs of estrogens of other classes of compounds and inhibitors of enzymes responsible for the metabolism of hormones.Keywords: 6-oxa-8α-analogs of steroid estrogens, their biological properties, NMR spectroscopy.In recent decades there have been attempts to create inhibitors of enzymes responsible for the metabolism of steroid hormones. The most important condition for the choice of new potential preparations is the absence in them of hormonal effects [1][2][3][4]. To solve these problems it is necessary to know what modifications in the structures of steroid hormones or their analogs lead to a sharp decrease in their hormonal activity or its complete disappearance. It is also important that the chose compounds should not have side effects typical for estrogens. In particular, hypertriglyceridemic effects should be absent since these independent risk factors for cardiovascular diseases [5].We have shown previously in experiments in ovariotomized rats that compound 1 possesses considerable hypertriglyceridemic activity, which is absent in compound 2 [6]. It is of interest to discover whether introduction of a methyl group in position 4 of other 6-oxa-8α-analogs of steroidal estrogens leads to a decrease in the negative influence of these substances on the triglyceride content.The 4-methyl-8α-analogs of estrogens 3 and 4 were chosen as model compounds for study since in the objective of obtaining optically active compounds is simpler in the case of compounds with a five-membered D ring. The biological activity of these compounds was compared with those of the "standard" substances 5 and 6 which have no substituents at position 4, and also with 17α-ethynylestradiol 7 which is frequently used in clinical practice. The synthesis of the required compounds is shown in the reaction scheme.