Banday Abid H, Shameem Shameem A, Banday Javid A, Ganaie Bashir A
Department of Chemistry, Islamia College of Science and Commerce, Srinagar 190002, India.
Centre of Research and Development, University of Kashmir, Hazratbal 190002, India.
Anticancer Agents Med Chem. 2018;18(13):1919-1926. doi: 10.2174/1871520618666180426100942.
The potential of steroids for development into lead pharmacological molecules lies in the regulation of a variety of biological processes by these molecules and also because of these being a fundamental class of signaling molecules. Steroid based scaffolds have been extensively used as active pharmaceutical agents for the treatment of various diseases including the deadly disease of cancer which despite the recent advances in the early diagnosis, prevention and therapy, remains a clinical challenge affecting millions of people world over and is one of the leading causes of death. It thus warrants the development of new drugs against this dreadful disease through exploitation of emerging molecularly defined targets.
The present study explores the effect of novel steroidal pyrazolines as presumed inhibitors of 5α- reductase (5AR) and 17α-hydroxylase-C-lyase as a target for treatment of prostate cancer. A series of 1,5- diaryl pyrazoline pregnenolones were synthesized and screened for 5α-reductase inhibitory activities. Synthesis of the analogs is multistep and proceeds in good overall yields. The key step in the synthesis of 1,5- disubstituted pyrazolinyl pregnenolones is the heterocyclization of bezylidine derivatives (3) in presence of phenylhydrazines (4) through the initial formation of the phenylhydrazones, which undergo concomitant cyclization to generate the stable pyrazoline derivatives.
All the synthesised D-ring 1,5-disubstituted pyrazolinyl pregnenolone derivatives (5a-l) were screened for prostate cancer cell inhibitory, 5α-reductase and 17α-hydroxylase-C-lyase inhibitory activity. Amongst all the compounds screened for their 5α-reductase inhibitory activities, compound 5c, 5e, 5g and 5l were found to be the most active. Further, compounds 5g and 5h were found to have moderate 17α-hydroxylase-C-lyase inhibitory activities.
A series of D-ring 1,5-disubstituted pyrazolinyl pregnenolone derivatives (5a-l) were synthesized and screened for their prostate cancer cell inhibitory, 5a-reductase and 17α-hydroxylase-C17,20-lyase inhibitory activity. Amongst all the compounds screened for their 5α-reductase inhibitory activities, compound 5c, 5e, 5g and 5l were found to be the most active whereas compounds 5g and 5h were found to have moderate 17α- hydroxylase-C-lyase inhibitory activities.
类固醇发展成为先导药物分子的潜力在于这些分子对多种生物过程的调节作用，还因为它们是一类基本的信号分子。基于类固醇的支架已被广泛用作活性药物，用于治疗包括致命疾病癌症在内的各种疾病。尽管在癌症的早期诊断、预防和治疗方面取得了最新进展，但癌症仍然是一个临床挑战，影响着全球数百万人，并且是主要的死亡原因之一。因此，有必要通过开发新出现的分子明确靶点来研发针对这种可怕疾病的新药。
本研究探索了新型甾体吡唑啉作为假定的5α-还原酶（5AR）和17α-羟化酶-C-裂解酶抑制剂对前列腺癌治疗的效果。合成了一系列1,5-二芳基吡唑啉孕烯醇酮，并筛选其5α-还原酶抑制活性。这些类似物的合成是多步骤的，总产率良好。1,5-二取代吡唑啉基孕烯醇酮合成中的关键步骤是苄叉基衍生物（3）在苯肼（4）存在下通过最初形成苯腙进行杂环化，苯腙随后伴随环化生成稳定的吡唑啉衍生物。
对所有合成的D环1,5-二取代吡唑啉基孕烯醇酮衍生物（5a-l）进行了前列腺癌细胞抑制、5α-还原酶和17α-羟化酶-C-裂解酶抑制活性的筛选。在所有筛选5α-还原酶抑制活性的化合物中，发现化合物5c、5e、5g和5l活性最高。此外，发现化合物5g和5h具有中等的17α-羟化酶-C-裂解酶抑制活性。
合成了一系列D环1,5-二取代吡唑啉基孕烯醇酮衍生物（5a-l），并筛选了它们的前列腺癌细胞抑制、5α-还原酶和17α-羟化酶-C17,20-裂解酶抑制活性。在所有筛选5α-还原酶抑制活性的化合物中，发现化合物5c、5e、5g和5l活性最高，而化合物5g和5h具有中等的17α-羟化酶-C-裂解酶抑制活性。
