Design, synthesis and antitumor activity of coumarin, isoxazole, pyrazole, pyridine and pyrimidine compounds: 3β-hydroxypregn-5-ene-20-one derivatives

IF 0.4 4区 医学 Q4 PHARMACOLOGY & PHARMACY Acta poloniae pharmaceutica Pub Date : 2023-05-04 DOI:10.32383/appdr/161430
K. El-Sharkawy, H. Alhazmi, A. Najmi, M. Albratty, A. Khalid, R. Hassani, S. Javed
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Abstract

In continuation of our reserach for synthesizing heterocyclic derivatives with a broad range of biological activities, the current research was performed to synthesize 3β-hydroxypregn-5-ene-20-one derivatives of coumarin, isoxazole, pyrazole, pyridine and pyrimidine and screen for antitumor activity. Synthesis of amino-thiopephen derivatives (1a-1b) was performed through reaction of 3β-hydroxypregn-5-ene-20-one with ethyl cyanoacetate or malononitrile and sulphur. 3β-Hydroxypregn-5-ene-20-one was reacted with ethyl cyanoacetate in the presence of hydrazine, urea or thiourea to obtain aminopyrazole (3), aminopyrimidine (4a-4b) derivatives, respectively. The amino-thiophene derivatives (1a-1b) further reacted with either phenylisothiocyanate or benzoylisothiocyanate to form fused thienopyrimidine derivatives (5a-5d). The products 1a and 1b were also treated with ethyl cyanoacetate to afford cyanoacetamidothiophene derivatives (6a-6b) which were converted to fused thienopyridone derivatives (7a-7b) through cyclization reaction. The compounds 6a and 6b were allowed to react with different carbonyl compounds including salicyaldehyde, cyclopentanone-sulphur mixture, acetylacetone and malonaldehyde to prepare coumarin (8a-8b), cyclopentylthiophene (9a-9b) and 2-pyridinone (10a-10d) derivatives respectively. Furthermore, the reactions of hydroxylamine hydrochloride and benzoylacetonitrile with the compounds 6a-6b separately afforded new aminoisoxazole (12a-12b) and phenylpyridone (14a-14b) derivatives, respectively. The structures of new products were established through IR, 1H NMR, 13C NMR spectroscopic and mass spectrometric analysis. The synthesized compounds (1a-1b to 14a-14b) displayed in-vitro antitumor activity against human cell-lines, including MCF-7 (breast adenocarcinoma), SF-268 (CNS cancer) and NCI-H460 (non-small lung cancer cell). The results suggested that all the screened products exhibited cell growth inhibitory activity in a dose-dependents manner. However, the compound 12a showed highest level of inhibition against all three cell-lines.
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香豆素、异恶唑、吡唑、吡啶和嘧啶类化合物:3β-羟基孕酮-5-烯-20- 1衍生物的设计、合成及其抗肿瘤活性
为了继续我们对具有广泛生物活性的杂环衍生物的合成研究,本研究对香豆素、异恶唑、吡唑、吡啶和嘧啶的3 - β-羟基孕酮-5-烯-20- 1衍生物进行了合成并进行了抗肿瘤活性筛选。通过3β-羟基孕酮-5-烯-20-酮与氰乙酸乙酯或丙二腈和硫的反应,合成了氨基噻吩衍生物(1a-1b)。3β-羟孕酮-5-烯-20- 1在肼、尿素或硫脲存在下与氰乙酸乙酯反应,分别得到氨基吡唑(3)、氨基嘧啶(4a-4b)衍生物。氨基噻吩衍生物(1a-1b)进一步与苯基异硫氰酸酯或苯甲酰异硫氰酸酯反应形成融合的噻吩嘧啶衍生物(5a-5d)。产物1a和1b也用氰乙酸乙酯处理得到氰乙酰氨基噻吩衍生物(6a-6b),并通过环化反应转化为熔融噻吩衍生物(7a-7b)。化合物6a和6b分别与水杨醛、环戊酮-硫混合物、乙酰丙酮和丙二醛等羰基化合物反应,分别制得香豆素(8a-8b)、环戊基噻吩(9a-9b)和2-吡啶酮(10a-10d)衍生物。此外,盐酸羟胺和苯甲酰乙腈分别与化合物6a-6b反应得到新的氨基异恶唑(12a-12b)和苯基吡酮(14a-14b)衍生物。通过IR、1H NMR、13C NMR和质谱分析确定了新产物的结构。合成的化合物(1a-1b至14a-14b)对人类细胞系,包括MCF-7(乳腺腺癌),SF-268(中枢神经系统癌)和NCI-H460(非小肺癌细胞)显示出体外抗肿瘤活性。结果表明,所有筛选的产物均表现出剂量依赖性的细胞生长抑制活性。然而,化合物12a对三种细胞系的抑制作用最高。
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来源期刊
CiteScore
0.80
自引率
0.00%
发文量
74
审稿时长
6-12 weeks
期刊介绍: The international journal of the Polish Pharmaceutical Society is published in 6 issues a year. The journal offers Open Access publication of original research papers, short communications and reviews written in English, in all areas of pharmaceutical sciences. The following areas of pharmaceutical sciences are covered: Analysis, Biopharmacy, Drug Biochemistry, Drug Synthesis, Natural Drugs, Pharmaceutical Technology, Pharmacology and General. A bimonthly appearing in English since 1994, which continues “Acta Poloniae Pharmaceutica”, whose first issue appeared in December 1937. The war halted the activity of the journal’s creators. Issuance of “Acta Poloniae Pharmaceutica” was resumed in 1947. From 1947 the journal appeared irregularly, initially as a quarterly, then a bimonthly. In the years 1963 – 1973 alongside the Polish version appeared the English edition of the journal. Starting from 1974 only works in English are published in the journal. Since 1995 the journal has been appearing very regularly in two-month intervals (six books a year). The journal publishes original works from all fields of pharmacy, summaries of postdoctoral dissertations and laboratory notes.
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