Recent advances in structure of progestins and their binding to progesterone receptors

Abstract

The role of progesterone in women's cancers as well as the knowledge of the progesterone receptor (PR) structure has prompted the design of different therapies. The aim of this review is to describe the basic structure of PR agonists and antagonists as well as the recent treatments for illness associated with the progesterone receptor. The rational design for potent and effective drugs for the treatment of female cancer must consider the structural changes of the androgen and progestogen skeleton which are an indicator of their activity as progestins or antiprogestins. The presence of a hydroxyl group at C-17 in the progesterone skeleton brings about a loss of progestational activity whereas acetylation induces a progestational effect. The incorporation of an ethynyl functional group to the testosterone framework results in a loss of androgenic activity with a concomitant enhancement of the progestational effect. On the other hand, an ester function at C-3 of dehydroepiandrosterone skeleton induces partial antagonism to the PR.

A Pregnane Steroid as the Chiral Auxiliary in 1,3‐Dipolar Azomethine Ylide's Cycloaddition: Asymmetric Synthesis and Anticancer Activity of Novel Hybrid Compounds

“…Targeted mechanism of action and tissue‐selective cytotoxicity determine the utility of different steroid derivatives in the chemotherapy of various neoplastic states . Different types of progestins, acting through modulating of progesterone receptors activity, have been used for endocrine therapy in patients with breast and gynecological cancers . Pregnane‐based progestins megestrol acetate (MA) and medroxyprogesterone acetate (MPA) are successfully used for decades for the treatment of breast and endometrial carcinomata.…”

“…[1] Different types of progestins, acting through modulating of progesterone receptors activity, have been used for endocrine therapy in patients with breast and gynecological cancers. [2,3] Pregnanebased progestins megestrol acetate (MA) and medroxyprogesterone acetate (MPA) are successfully used for decades for the treatment of breast [4] and endometrial [5] carcinomata. Novel derivatives of MA with confirmed high progestational activity were synthesized by reductive/acylative modification of C3 position of the pregnane molecular framework (i. e. acetomepregenol 1 a and butagest 1 b (Figure 1)).…”

Impact of menstrual cycle phase and oral contraceptives on sleep and overnight memory consolidation

“…This observation is not surprising since progestins, synthetic gestagens in OCs, are metabolized more slowly (Devoto et al., 2005 ; Kook et al., 2002 ; Kuhl, 2005 ; Schindler, 2011 ) and in different ways than endogenous progesterone (Giatti et al., 2016 ). Progestins also bind to progesterone receptors (Harada & Taniguchi, 2010 ; Kloosterboer et al., 1988 ) and sometimes have higher binding affinities to the progesterone receptors (Cabeza et al., 2015 ; Harada & Taniguchi, 2010 ; Lovett et al., 2017 ; Regidor & Schindler, 2017 ). In addition, the synthetic progestins are consistently high over the 3 weeks of intake, whereas the progesterone levels in naturally cycling women rise after ovulation, reach a peak during the mid‐luteal phase and decrease before the next menses (Le et al., 2020 ).…”

“…Although the endogenous progesterone level in women using OCs is low, the OCs contain very potent synthetic progestins that also bind to progesterone receptors (Harada & Taniguchi, 2010 ; Kloosterboer et al., 1988 ). Synthetic progestins can have higher binding affinities to the progesterone receptors (Cabeza et al., 2015 ; Lovett et al., 2017 ) and longer elimination half‐lives than endogenous progesterone (Devoto et al., 2005 ; Kook et al., 2002 ; Kuhl, 2005 ; Regidor & Schindler, 2017 ; Schindler, 2011 ). The hormonal progestin exposure in some OCs is four times higher than the endogenous progesterone exposure (Lovett et al., 2017 ).…”

Effects of menopausal hormone therapy-based on the role of estrogens, progestogens, and their metabolites in proliferation of breast cancer cells

“…MPA is a synthetic derivative of P4, and its progestogenic effect is similar to that of P4. However, even small structural changes might cause large variations in the functional effects of a molecule; for example, when compared with P4, MPA shows a relatively high progestogen activity when a methyl group is added to C6 93 .…”