| Reference | [1]. ACS Omega. 2019 Nov 5;4(21):19382-19398. doi: 10.1021/acsomega.9b02789. eCollection 2019 Nov 19.<br />
Imidazo[2,1-b]thiazole-Coupled Natural Noscapine Derivatives as Anticancer Agents.<br />
Nagireddy PKR(1), Kommalapati VK(1), Siva Krishna V(2), Sriram D(2), Tangutur AD(1)(3), Kantevari S(1)(3).<br />
Author information: (1)Fluoro and Agrochemicals Division and Applied Biology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, Telangana, India. (2)Medicinal Chemistry and Antimycobacterial Research Laboratory, Pharmacy Group, Birla Institute of Technology & Science Pilani, Hyderabad Campus, Hyderabad 500078, Telangana, India. (3)Academy of Scientific and Innovative Research (AcSIR), Chennai 600113, Tamil Nadu, India.<br />
Noscapine, a phthalide isoquinoline alkaloid isolated from the opium poppy Papaver somniferum, is traditionally being used as an anticough drug. With a safe in vitro toxicological profile, noscapine and its analogues have been explored to show microtubule-regulating properties and anticancer activity against various mammalian cancer cell lines. Since then, our group and other research groups worldwide are working on developing new noscapinoids to tap its potential as the leading drug molecule. With our continuing efforts, we herein present synthesis and anticancer evaluation of a series of imidazothiazole-coupled noscapinoids 7a-o and 11a-o. Natural α-noscapine was N-demethylated to nornoscapine 4 and then reacted with 4-(chloromethyl) thiazole-2-amine. The resultant noscapinoid 5 was coupled with various bromomethyl ketones 10a-o to give N-imidazothiazolyl noscapinoids 7a-o in very good yields. Similarly, natural α-noscapine 1 was O-demethylated using sodium azide/sodium iodide, reacted with 4-(chloromethyl)thiazole-2-amine, and coupled with bromomethyl ketones 10a-o to result in O-imidazothiazolyl noscapinoids 11a-o. All the new analogues 7a-o and 11a-o were fully characterized by their NMR and mass spectral analysis. In vitro cytotoxicity assay was performed for compounds 5, 7a-o, 9, and 11a-o against four different cancer cell lines: HeLa (cervical), MIA PaCa-2 (pancreatic), SK-N-SH (neuroblastoma), and DU145 (prostate cancer). Among these conjugates, 5, 7a, 9, 11b, 11c, 11e, and 11o showed potent cytotoxicity with low IC50 values. Further, flow cytometry analysis revealed that MIA PaCa-2 cells treated with these compounds induced cell cycle G2/M-phase arrest. In addition, Western blot analysis revealed that the cells treated with these conjugates accumulate tubulin in the soluble fraction and also elevate cyclin-B1 protein expression levels. Moreover, the conjugates also increased the expression of caspase-3 and PARP levels which is indicative of apoptotic cell death. In silico molecular docking studies showed several noncovalent interactions like van der Waals and hydrogen-bonding with tubulin protein and with good binding energy. The results indicated that these noscapine analogues may serve as novel compounds that can possibly inhibit tubulin protein and can be considered for further optimization as a clinical candidate for treating pancreatic cancer.<br />
DOI: 10.1021/acsomega.9b02789 PMCID: PMC6868913 PMID: 31763563<br />
<br />
[2]. J Med Chem. 1998 Nov 19;41(24):4854-60. doi: 10.1021/jm9804580.<br />
1,2-Benzisothiazol-3-one 1,1-dioxide inhibitors of human mast cell tryptase.<br />
Combrink KD(1), Gülgeze HB, Meanwell NA, Pearce BC, Zulan P, Bisacchi GS, Roberts DG, Stanley P, Seiler SM.<br />
Author information: (1)Department of Central Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, Connecticut 06492-1927, USA.<br />
A library of compounds were prepared by reacting 2-(bromomethyl)-1, 2-benzisothiazol-3(2H)-one 1,1-dioxide (5) with commercially available carboxylic acids in the presence of potassium carbonate or a tertiary amine base. From this library, (1,1-dioxido-3-oxo-1, 2-benzisothiazol-2(3H)-yl)methyl N-[(phenylmethoxy)carbonyl]-beta-alanate (7b) emerged as a potent inhibitor of human mast cell tryptase (IC50 = 0.85 microM). Extension of the side chain of 7b by two carbons gave (1, 1-dioxido-3-oxo-1,2-benzisothiazol-2(3H)-yl)methyl 5-[[(phenylmethoxy)carbonyl]amino]pentanoate (7d) which was an 8-fold more potent inhibitor (IC50 = 0.1 microM). Further modification of this series produced benzoic acid derivative (1, 1-dioxido-3-oxo-1,2-benzisothiazol-2(3H)-yl)methyl 4-[[(phenylmethoxy)carbonyl]amino]benzoate (7n) which is the most potent inhibitor identified in this series (IC50 = 0.064 microM). These compounds exhibit time-dependent inhibition consistent with mechanism-based inhibition. For 7b, the initial enzyme velocity is not a saturable function of the inhibitor concentration and the initial Ki could not be determined (Ki > 10 microM). The steady-state rate constant, Ki, was determined to be 396 nM. On the other hand, compounds 7d and 7n are time-dependent inhibitors with a saturable initial complex. From these studies, an initial rate constant, Ki, for 7d and 7n was found to be 345 and 465 nM, respectively. The steady-state inhibition constants, Ki, for 7d and 7n were calculated to be 60 and 52 nM, respectively. Compound 7n is a 13-fold more potent inhibitor than 7b, and these kinetic studies indicate that the increase in inhibitory activity is due to an increase in initial affinity toward the enzyme and not an increase in chemical reactivity. These inhibitors generally show high selectivity for tryptase, being 40-fold weaker inhibitors of elastase, being 100-fold weaker against trypsin, and showing no inhibition against thrombin. These compounds are not inhibitors of thrombin, plasmin t-PA, urokinase, and factor Xa (IC50 > 33 microM). In the delayed-type hypersensitivity (DTH) mouse model, a model of skin inflammation, a 5% solution of 7d reduced edema by 69% compared to control animals.<br />
DOI: 10.1021/jm9804580 PMID: 9822554 [Indexed for MEDLINE]<br />
<br />
[3]. Molecules. 2018 Dec 11;23(12):3285. doi: 10.3390/molecules23123285.<br />
Synthesis, Antibacterial, and Anti HepG2 Cell Line Human Hepatocyte Carcinoma Activity of Some New Potentially Benzimidazole-5-(Aryldiazenyl)Thiazole Derivatives.<br />
Khalifa ME(1), Gobouri AA(2), Kabli FM(3), Altalhi TA(4), Almalki ASA(5), Mohamed MA(6).<br />
Author information: (1)Department of Chemistry, faculty of Science, Taif University, Taif 21974, Saudi Arabia. [email protected]. (2)Department of Chemistry, faculty of Science, Taif University, Taif 21974, Saudi Arabia. [email protected]. (3)Department of Chemistry, faculty of Science, Taif University, Taif 21974, Saudi Arabia. [email protected]. (4)Department of Chemistry, faculty of Science, Taif University, Taif 21974, Saudi Arabia. [email protected]. (5)Department of Chemistry, faculty of Science, Taif University, Taif 21974, Saudi Arabia. [email protected]. (6)Department of Biochemistry, Faculty of Agriculture, Cairo University, Giza 12613, Egypt. [email protected].<br />
The paper describes the synthesis and biological evaluation of some new benzimidazole derivatives as potent clinical drugs that are useful in the treatment of some microbial infections and tumor inhibition. The starting compound 2-(bromomethyl)-1H-benzimidazole (1) was prepared, and hence underwent interesting functionalization reactions to afford several series of benzimidazole-5-(aryldiazenyl)thiazole derivatives: 3a⁻c, 7a⁻c, and 8a⁻c. The antibacterial activities of the synthesized compounds were evaluated by calculation of the inhibition zone diameter (mm) and the determination of minimum inhibitory concentration (µg/mL) against selected pathogenic bacteria Staphylococcus aureus (Gram-positive bacteria) and Escherichia coli (Gram-negative bacteria).Noticeable efficiency was found based on in vitro screening for their antioxidant activity and cytotoxicity effect against the human liver cancer cell line (HepG2) and human hepatocyte carcinoma cells at relatively high concentrations.<br />
DOI: 10.3390/molecules23123285 PMCID: PMC6321333 PMID: 30544987 [Indexed for MEDLINE]
|
