Synthesis and Cytostatic Activity of some Pregna-D′-Pentaranes on HeLa Cell Culture

Abstract

The effects of nine new pregnane steroids containing substituents in the 16a,17a-and/or 3-, 6-, and 19-positions of the steroid framework on the viability of HeLa cervical cancer cells were studied. It was shown that the 6-oximes of 3-keto-and 3-hydroxy-4-dehydrosteroids with a 16a,17a-cyclohexane substituent and 3-keto-4-dehydrosteroids with a 16a,17a-phenylcyclopropane substituent reduced the viability of the cell culture. Compound K1047 had the highest cytostatic effect and was promising as a potential hormonal antitumor agent.Progesterone derivatives are widely used in oncogynecological practice [1]. Therefore, the design of new domestic compounds for hormone therapy of oncological diseases is a crucial problem in pharmacology.Progesterone derivatives containing additional carbon rings D¢ in the 16a,17a-positions of the steroid skeleton (pregna-D¢-pentaranes) represent a promising class of progesterone receptor (PR) ligands [2]. The effect of progestins on the growth of tumor cells in culture can be used as a preliminary assessment of their antitumor activity.According to the literature, progestins inhibit estradiolstimulated proliferation of human breast and cervical cancer cells in cultures [3]. Earlier, we showed that pregnane-type 3-keto-4-dehydrosteroids with a 16a,17a-spiropentane substituent and 3-keto-4-dehydro-16a,17a-cyclohexanopregnanes with a 3-or 19-oxime or a methoxyimine group reduced the viability of MCF-7 breast and HeLa cervical cancer cells in cultures [4].Herein the cytostatic activity of nine new pregna-D¢-pentaranes that were synthesized at Zelinsky Institute of Organic Chemistry, RAS, in the Laboratory of Steroid Chemistry was studied (Fig. 1).Compounds II-V were synthesized as shown in the scheme. Compounds I and VI-IX were synthesized by the literature methods [2,5].The starting material for synthesizing 6-substituted pentaranes II-V was the 5a,6a-epoxide (X) that we described previously [6]. Opening of it gave diol XI, oxidation of the 6-OH of which by Jones reagent produced 6-ketopentarane XII. Then, cleavage of the 5a-OH and hydrolysis of the 3-O-acetate afforded 4,5-dehydro-3-hydroxy-6,20-dioxopentarane XIII, which reacted with hydroxylamine hydrochloride or O-methylhydroxylamine to give oximes II and IV, respectively. The oximes were oxidized using pyridinium dichromate (PDC) in Py to produce the corresponding 3-ketones III and V. The structures of all synthesized compounds were derived from physicochemical analyses. 6-Oximes II-V were assigned the E-configuration based on the characteristic resonance of the C7 equatorial proton as a doublet at d 3.33 ppm (J 14.0 and 4.0 Hz) [6,7]. 363 0091-150X/14/4806-0363

Clinical Use of Progestins and Their Mechanisms of Action: Present and Future (Review)

“…Progesterone inhibits TRPM7 expression, thereby switching acidotoxic necrosis of tumor cells to apoptosis [ 66 ]. A number of studies on HeLa cells have demonstrated the cytotoxic effect not only of progesterone, but also of its synthetic derivatives, the cytotoxic effect being observed both upon stimulation with estradiol and without stimulation [ 67 , 68 ].…”