- Hemisynthesis, computational and molecular docking studies of novel nitrogen containing steroidal aromatase inhibitors: Testolactam and testololactam
-
Testololactone (10) and testolactone (11) represent aromatase inhibitors containing lactone rings. We previously reported their hemisynthesis from the most common phytosterols, which are highly abundant in nature. Herein, we report the synthesis of their nitrogen congeners: testololactam (3) and testolactam (8). The reaction process involves the conversion of 4-androstene-3,17-dione to its corresponding oxime using hydroxylamine hydrochloride, whose Beckmann rearrangement under acid conditions yielded the desired testololactam (3). However, testolactam (8) was formed by the Beckmann rearrangement of the oxime (7) of 1,4-androstene-3,17-dienone (6). This expeditious reaction scheme may be exploited for the bulk production of testololactam (3) and testolactam (8). Theoretical DFT studies concerning the structural and electronic properties of all the end products were carried out using the Becke three-parameter Lee-Yang-Parr function (B3LYP) and 6-31G(d,p) level of theory. Molecular electrostatic potential map and frontier orbital analysis were carried out. The HOMO-LUMO energy gap was calculated, which allowed the calculation of relative reactivity descriptors like chemical hardness, chemical inertness, chemical potential, nucleophilicity and electrophilicity index of the synthesized products. The molecular docking studies of testololactam (3), testolactam (8) and testololactone (10), with aromatase (CYP19) revealed binding free energies of (ΔGb) = -9.85, -9.62 and -10.14 kcal mol-1 respectively, compared to the standard testolactone (11), a well-known aromatase inhibitor sold under the brand name TESLAC, which exhibited a binding free energy (ΔGb) of -10.29 kcal mol-1 with an inhibition constant Ki of 28.87 nM. The docking study revealed that the nitrogen congeners exhibit a relatively lower but appreciable therapeutic efficiency to be used as aromatase inhibitors.
- Lone, Shabir H.,Bhat, Muzzaffar A.,Lone, Rayees A.,Jameel, Salman,Lone, Javeed A.,Bhat, Khursheed A.
-
-
Read Online
- Synthesis and biological evaluation of 3-tetrazolo steroidal analogs: Novel class of 5α-reductase inhibitors
-
In the present study, a series of steroidal tetrazole derivatives of androstane and pregnane have been prepared in which the tetrazole moiety was appended at C-3 and 17a-aza locations. 3-Tetrazolo-3,5-androstadien-17-one (6), 3-tetrazolo-19-nor-3,5-androstadien-17-one (10), 3-tetrazolo-3,5-pregnadien-20-one (14), 17a-substituted 3-tetrazolo-17a-aza-d-homo-3,5-androstadien-17-one (26-31) and 3-(2-acetyltetrazolo)-17a-aza-d-homo-3,5-androstadien-17-one (32) were synthesized from dehydroepiandrosterone acetate (1) through multiple synthetic steps. Some of the synthesized compounds were evaluated for their in vitro 5α-reductase (5AR) inhibitory activity by measuring the conversion of [3H] androstenedione in human embryonic kidney (HEK) cells. In vivo 5α-reductase inhibitory activity also showed a significant reduction (p 50 being 15.6 nM as compared to clinically used drug finasteride (40 nM). There was also a significant inhibition of 5AR-1 with IC50 547 nM compared to finasteride (453 nM).
- Aggarwal, Saurabh,Mahapatra, Manoj Kumar,Kumar, Rajnish,Bhardwaj, Tilak R.,Hartmann, Rolf W.,Haupenthal, J?rg,Kumar, Manoj
-
p. 779 - 788
(2016/02/09)
-
- Synthesis and biological evaluation of novel unsaturated carboxysteroids as human 5α-reductase inhibitors: A legitimate approach
-
In the present study, novel steroidal 17a-substituted 3-cyano-17a-aza-D- homo-3,5-androstadien-17-ones (12-19) and 17a-substituted 17-oxo-17a-aza-D-homo- 3,5-androstadien-3-oic acids (20-26) were synthesized from dehydroepiandrosterone acetate (6) along with 17-oxo-19-nor-3,5-androstadien-3- oic acid (30) through a multistep synthesis. Compounds were evaluated for their in vitro 5α-reductase inhibitory activity by measuring the conversion of [3H] androstenedione in human embryonic kidney (HEK) cells. In vivo 5α-reductase inhibitory activity was also determined using rat prostate weighing method. Compounds 21-23 and 25 showed potent inhibition of 5α-reductase II enzyme with IC50 values of 54.1 ± 9.5, 22.1 ± 2.4, 72.8 ± 2.3 and 26.5 ± 4.4 nM respectively as compared to Finasteride (30.3 nM) along with a significant (p 0.05) reduction in rat prostate weight.
- Aggarwal, Saurabh,Thareja, Suresh,Bhardwaj,Haupenthal, Joerg,Hartmann,Kumar, Manoj
-
p. 728 - 739
(2012/09/22)
-