{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T02:30:12Z","timestamp":1791945012230,"version":"4.3.4"},"reference-count":43,"publisher":"American Chemical Society (ACS)","issue":"21","license":[{"start":{"date-parts":[[2019,11,5]],"date-time":"2019-11-05T00:00:00Z","timestamp":1572912000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/pubs.acs.org\/page\/policy\/authorchoice_termsofuse.html"}],"funder":[{"DOI":"10.13039\/501100001501","name":"University Grants Commission","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/501100001501","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001843","name":"Science and Engineering Research Board","doi-asserted-by":"publisher","award":["EMR\/2017\/002946"],"award-info":[{"award-number":["EMR\/2017\/002946"]}],"id":[{"id":"10.13039\/501100001843","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,11,19]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>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\u2013o and 11a\u2013o. Natural \u03b1-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\u2013o to give N-imidazothiazolyl noscapinoids 7a\u2013o in very good yields. Similarly, natural \u03b1-noscapine 1 was O-demethylated using sodium azide\/sodium iodide, reacted with 4-(chloromethyl)thiazole-2-amine, and coupled with bromomethyl ketones 10a\u2013o to result in O-imidazothiazolyl noscapinoids 11a\u2013o. All the new analogues 7a\u2013o and 11a\u2013o were fully characterized by their NMR and mass spectral analysis. In vitro cytotoxicity assay was performed for compounds 5, 7a\u2013o, 9, and 11a\u2013o 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.<\/jats:p>","DOI":"10.1021\/acsomega.9b02789","type":"journal-article","created":{"date-parts":[[2019,11,5]],"date-time":"2019-11-05T16:11:49Z","timestamp":1572970309000},"page":"19382-19398","source":"Crossref","is-referenced-by-count":34,"title":["Imidazo[2,1-\n                    <i>b<\/i>\n                    ]thiazole-Coupled\nNatural Noscapine Derivatives as Anticancer Agents"],"prefix":"10.1021","volume":"4","author":[{"given":"Praveen Kumar Reddy","family":"Nagireddy","sequence":"first","affiliation":[{"name":"CSIR-Indian Institute of Chemical Technology , , , ,","place":["Hyderabad, Telangana, India, 500007"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vamsi Krishna","family":"Kommalapati","sequence":"additional","affiliation":[{"name":"CSIR-Indian Institute of Chemical Technology , , , ,","place":["Hyderabad, Telangana, India, 500007"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vagolu","family":"Siva Krishna","sequence":"additional","affiliation":[{"name":"Birla Institute of Technology & Science Pilani , , Hyderabad Campus , , ,","place":["Hyderabad, Telangana, India, 500078"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dharmarajan","family":"Sriram","sequence":"additional","affiliation":[{"name":"Birla Institute of Technology & Science Pilani , , Hyderabad Campus , , ,","place":["Hyderabad, Telangana, India, 500078"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anjana Devi","family":"Tangutur","sequence":"additional","affiliation":[{"name":"CSIR-Indian Institute of Chemical Technology , , , ,","place":["Hyderabad, Telangana, India, 500007"]},{"name":"Academy of Scientific and Innovative Research (AcSIR) , , ,","place":["Chennai, Tamil Nadu, India, 600113"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4270-9651","authenticated-orcid":true,"given":"Srinivas","family":"Kantevari","sequence":"additional","affiliation":[{"name":"CSIR-Indian Institute of Chemical Technology , , , ,","place":["Hyderabad, Telangana, India, 500007"]},{"name":"Academy of Scientific and Innovative Research (AcSIR) , , ,","place":["Chennai, Tamil Nadu, India, 600113"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2019,11,5]]},"reference":[{"key":"2026090209445934700_cit1","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1016\/j.canlet.2017.03.024","article-title":"Galectin-1-driven upregulation\nof SDF-1 in pancreatic stellate cells promotes pancreatic cancer metastasis","volume":"397","author":"Qian","year":"2017","journal-title":"Cancer Lett."},{"key":"2026090209445934700_cit2","doi-asserted-by":"publisher","first-page":"7","DOI":"10.3322\/caac.21332","article-title":"Cancer statistics,\n2016","volume":"66","author":"Siegel","year":"2016","journal-title":"Ca\u2500Cancer J. Clin."},{"key":"2026090209445934700_cit3","doi-asserted-by":"publisher","first-page":"E359","DOI":"10.1002\/ijc.29210","article-title":"Cancer incidence\nand mortality worldwide: sources, methods and major patterns in GLOBOCAN\n2012","volume":"136","author":"Ferlay","year":"2015","journal-title":"Int. J. Cancer"},{"key":"2026090209445934700_cit4","doi-asserted-by":"publisher","first-page":"2913","DOI":"10.1158\/0008-5472.can-14-0155","article-title":"Projecting cancer incidence and deaths\nto 2030: the unexpected burden of thyroid, liver, and pancreas cancers\nin the United States","volume":"74","author":"Rahib","year":"2014","journal-title":"Cancer Res."},{"key":"2026090209445934700_cit5","doi-asserted-by":"publisher","first-page":"1241","DOI":"10.21873\/anticanres.12345","article-title":"Centrosomal\nabnormalities in pancreatic cancer: molecular mechanisms and clinical\nimplications","volume":"38","author":"Ansari","year":"2018","journal-title":"Anticancer Res."},{"key":"2026090209445934700_cit6","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1016\/j.canlet.2018.12.005","article-title":"Cancer-associated\nacinar-to-ductal metaplasia within\nthe invasive front of pancreatic cancer contributes to local invasion","volume":"444","author":"Kibe","year":"2019","journal-title":"Cancer Lett."},{"key":"2026090209445934700_cit7","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/nrdp.2016.22","article-title":"Pancreatic\nCancer","volume":"2","author":"Kleeff","year":"2016","journal-title":"Nat. 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Chem."},{"key":"2026090209445934700_cit10","doi-asserted-by":"publisher","first-page":"92","DOI":"10.2174\/157489209787002524","article-title":"The anti-cancer\nactivity of noscapine: a review","volume":"4","author":"Mahmoudian","year":"2009","journal-title":"Recent Pat.\nAnticancer Drug Discov."},{"key":"2026090209445934700_cit11","doi-asserted-by":"publisher","first-page":"40518","DOI":"10.18632\/oncotarget.9642","article-title":"A new antiproliferative noscapine\nanalogue: chemical\nsynthesis and biological evaluation","volume":"7","author":"Ghaly","year":"2016","journal-title":"Oncotarget"},{"key":"2026090209445934700_cit12","doi-asserted-by":"publisher","first-page":"2122","DOI":"10.1002\/cmdc.201200365","article-title":"Synthesis and Biological Evaluation\nof N-Substituted\nNoscapine Analogues","volume":"7","author":"DeBono","year":"2012","journal-title":"ChemMedChem"},{"key":"2026090209445934700_cit13","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1002\/cmdc.201300395","article-title":"The synthesis\nand biological evaluation of multifunctionalised\nderivatives of noscapine as cytotoxic agents","volume":"9","author":"DeBono","year":"2014","journal-title":"ChemMedChem"},{"key":"2026090209445934700_cit14","doi-asserted-by":"publisher","first-page":"649","DOI":"10.1139\/cjc-2016-0649","article-title":"Synthesis\nand biological evaluation of structurally simplified noscapine analogues\nas microtubule binding agents","volume":"95","author":"Ghaly","year":"2017","journal-title":"Can. J. Chem."},{"key":"2026090209445934700_cit15","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1016\/j.bcp.2006.05.004","article-title":"Synthesis of microtubule-interfering halogenated noscapine\nanalogs that perturb mitosis in cancer cells followed by cell death","volume":"72","author":"Aneja","year":"2006","journal-title":"Biochem. Pharmacol."},{"key":"2026090209445934700_cit16","doi-asserted-by":"publisher","first-page":"2756","DOI":"10.1021\/jm0494220","article-title":"Discovery of S-phase\narresting agents derived from\nnoscapine","volume":"48","author":"Anderson","year":"2005","journal-title":"J. Med. Chem."},{"key":"2026090209445934700_cit17","doi-asserted-by":"publisher","first-page":"7096","DOI":"10.1021\/jm050674q","article-title":"Identification of novel and improved\nantimitotic agents derived from noscapine","volume":"48","author":"Anderson","year":"2005","journal-title":"J.\nMed. Chem."},{"key":"2026090209445934700_cit18","doi-asserted-by":"publisher","first-page":"1920","DOI":"10.1021\/jm200848t","article-title":"Tubulin binding,\nprotein-bound conformation in solution, and antimitotic cellular profiling\nof noscapine and its derivatives","volume":"55","author":"Bennani","year":"2012","journal-title":"J. Med. Chem."},{"key":"2026090209445934700_cit19","doi-asserted-by":"publisher","first-page":"8444","DOI":"10.1021\/acs.jmedchem.8b00986","article-title":"Synthesis\nand Pharmacological Evaluation of Noscapine-Inspired 5-Substituted\nTetrahydroisoquinolines as Cytotoxic Agents","volume":"61","author":"Devine","year":"2018","journal-title":"J. Med. Chem."},{"key":"2026090209445934700_cit20","doi-asserted-by":"publisher","first-page":"666","DOI":"10.1016\/j.ejmech.2014.12.012","article-title":"Imidazothiazole\nand related heterocyclic\nsystems. Synthesis, chemical and biological properties","volume":"90","author":"Fascio","year":"2015","journal-title":"Eur. J. Med. Chem."},{"key":"2026090209445934700_cit21","doi-asserted-by":"publisher","first-page":"908","DOI":"10.1002\/jps.2600740836","article-title":"Immune\nModulation Agents and Their Mechanisms Immunology Series","volume":"74","author":"Ades","year":"1985","journal-title":"J. Pharm. Sci."},{"key":"2026090209445934700_cit22","doi-asserted-by":"publisher","first-page":"6480","DOI":"10.1002\/slct.201701563","article-title":"Development and Biological Evaluation\nof Imidazothiazole propenones\nas Tubulin Inhibitors that Effectively Triggered Apoptotic Cell Death\nin Alveolar Lung Cancer Cell Line","volume":"2","author":"Sayeed","year":"2017","journal-title":"ChemistrySelect"},{"key":"2026090209445934700_cit23","doi-asserted-by":"publisher","first-page":"3085","DOI":"10.1021\/jm040888s","article-title":"Potential Antitumor Agents. 37. Synthesis\nand Antitumor Activity of Guanylhydrazones from Imidazo [2,1-b] thiazoles\nand from the New Heterocyclic System Thiazolo [2\u2018, 3\u2018:\n2, 3] imidazo [4,5-c] quinoline","volume":"48","author":"Andreani","year":"2005","journal-title":"J. Med. Chem."},{"key":"2026090209445934700_cit24","doi-asserted-by":"publisher","first-page":"4311","DOI":"10.1016\/j.ejmech.2011.07.001","article-title":"Imidazo [2, 1-b] thiazole guanylhydrazones as RSK2\ninhibitors","volume":"46","author":"Andreani","year":"2011","journal-title":"Eur. J. Med. Chem."},{"key":"2026090209445934700_cit25","doi-asserted-by":"publisher","first-page":"2766","DOI":"10.1002\/cmdc.201402310","article-title":"Design\nand Synthesis of Imidazo [2,1-b] thiazole-Chalcone\nConjugates: Microtubule- Destabilizing Agents","volume":"9","author":"Kamal","year":"2014","journal-title":"ChemMedChem"},{"key":"2026090209445934700_cit26","doi-asserted-by":"publisher","first-page":"2078","DOI":"10.1021\/jm2012694","article-title":"Substituted 3-(5-imidazo [2,1-b]\nthiazolylmethylene)-2-indolinones and analogues: synthesis, cytotoxic\nactivity, and study of the mechanism of action","volume":"55","author":"Andreani","year":"2012","journal-title":"J. Med. Chem."},{"key":"2026090209445934700_cit27","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1016\/j.ejmech.2014.09.051","article-title":"Recent developments\nin tubulin polymerization inhibitors: an overview","volume":"87","author":"Kaur","year":"2014","journal-title":"Eur. J. Med. Chem."},{"key":"2026090209445934700_cit28","doi-asserted-by":"publisher","first-page":"1842","DOI":"10.1039\/c5md00155b","article-title":"Aryl-imidazothiadiazole\nanalogues as microtubule disrupting\nagents","volume":"6","author":"Kamal","year":"2015","journal-title":"MedChemComm"},{"key":"2026090209445934700_cit29","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1016\/j.canlet.2005.06.037","article-title":"YM-201627: An orally active antitumor\nagent with selective inhibition of vascular endothelial cell proliferation","volume":"238","author":"Amino","year":"2006","journal-title":"Cancer Lett."},{"key":"2026090209445934700_cit30","doi-asserted-by":"publisher","first-page":"7808","DOI":"10.1021\/jm9007533","article-title":"Identification\nof N-(5-tert-butyl-isoxazol-3-yl)-N\u2032-{4-[7-(2-morpholin-4-yl-ethoxy)\nimidazo [2,1-b][1,3] benzothiazol-2-yl] phenyl} urea dihydrochloride\n(AC220), a uniquely potent, selective, and efficacious FMS-like tyrosine\nkinase-3 (FLT3) inhibitor","volume":"52","author":"Chao","year":"2009","journal-title":"J. Med. Chem."},{"key":"2026090209445934700_cit31","doi-asserted-by":"publisher","first-page":"e77970","DOI":"10.1371\/journal.pone.0077970","article-title":"Rational design, synthesis, and biological\nevaluation of third generation \u03b1-noscapine analogues as potent\ntubulin binding anti-cancer agents","volume":"8","author":"Manchukonda","year":"2013","journal-title":"PLoS One"},{"key":"2026090209445934700_cit32","doi-asserted-by":"publisher","first-page":"4092","DOI":"10.1002\/slct.201900666","article-title":"Synthesis\nand Antiproliferative Activity of 9-Formyl and 9-Ethynyl Noscapines","volume":"4","author":"Reddy Nagireddy","year":"2019","journal-title":"ChemistrySelect"},{"key":"2026090209445934700_cit33","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1016\/j.bcp.2011.03.029","article-title":"Second generation benzofuranone ring\nsubstituted noscapine analogs: synthesis and biological evaluation","volume":"82","author":"Mishra","year":"2011","journal-title":"Biochem. Pharmacol."},{"key":"2026090209445934700_cit34","doi-asserted-by":"publisher","first-page":"2216","DOI":"10.1182\/blood-2005-12-5142","article-title":"Microtubules,\nleukemia, and cough syrup","volume":"107","author":"Heidemann","year":"2006","journal-title":"Blood"},{"key":"2026090209445934700_cit35","first-page":"522","article-title":"Study of Noscapine-Induced\nCell Death in Hepatocellular Carcinoma Cell Line","volume":"3","author":"Tayarani-Najaran","year":"2009","journal-title":"Pharmacologyonline"},{"key":"2026090209445934700_cit36","doi-asserted-by":"publisher","first-page":"6751","DOI":"10.1021\/jm200639r","article-title":"Design and synthesis of resveratrol-based\nnitrovinylstilbenes\nas antimitotic agents","volume":"54","author":"Reddy","year":"2011","journal-title":"J. Med. Chem."},{"key":"2026090209445934700_cit37","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1016\/s0959-437x(05)80318-1","article-title":"Cell cycle\ncontrol in normal and neoplastic cells","volume":"2","author":"Morgan","year":"1992","journal-title":"Curr.\nOpin. Genet. Dev."},{"key":"2026090209445934700_cit38","doi-asserted-by":"publisher","first-page":"1821","DOI":"10.1126\/science.7997877","article-title":"Cell cycle control\nand cancer","volume":"266","author":"Hartwell","year":"1994","journal-title":"Science"},{"key":"2026090209445934700_cit39","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1046\/j.1365-2184.2000.00191.x","article-title":"Cell cycle\ncheckpoints and their inactivation in human cancer","volume":"33","author":"Molinari","year":"2000","journal-title":"Cell Proliferation"},{"key":"2026090209445934700_cit40","doi-asserted-by":"publisher","first-page":"4489","DOI":"10.1021\/cr010183n","article-title":"Caspases: keys in\nthe ignition of cell death","volume":"102","author":"Denault","year":"2002","journal-title":"Chem. Rev."},{"key":"2026090209445934700_cit41","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1038\/sj.cdd.4400476","article-title":"Emerging roles of caspase-3 in apoptosis","volume":"6","author":"Porter","year":"1999","journal-title":"Cell Death Differ."},{"key":"2026090209445934700_cit42","doi-asserted-by":"publisher","first-page":"6177","DOI":"10.1021\/jm051256o","article-title":"Extra Precision\nGlide: Docking and Scoring Incorporating a Model of Hydrophobic Enclosure\nfor Protein\u2013Ligand Complexes","volume":"49","author":"Friesner","year":"2006","journal-title":"J. Med.\nChem."},{"key":"2026090209445934700_cit43","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1007\/s10822-019-00184-1","article-title":"Discovery\nand evaluation of novel Mycobacterium tuberculosis ketol-acid reductoisomerase\ninhibitors as therapeutic drug leads","volume":"33","author":"Krishna","year":"2019","journal-title":"J. Comput.-Aided\nMol. Des."}],"container-title":["ACS Omega"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acsomega.9b02789","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/acsodf\/article-pdf\/4\/21\/19382\/67773623\/acsomega.9b02789.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/acsodf\/article-pdf\/4\/21\/19382\/67773623\/acsomega.9b02789.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T13:45:11Z","timestamp":1788356711000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/acsodf\/article\/4\/21\/19382\/608688\/Imidazo-2-1-b-thiazole-Coupled-Natural-Noscapine"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,11,5]]},"references-count":43,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2019,11,5]]},"published-print":{"date-parts":[[2019,11,19]]}},"URL":"https:\/\/doi.org\/10.1021\/acsomega.9b02789","relation":{},"ISSN":["2470-1343"],"issn-type":[{"value":"2470-1343","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,11,5]]}}}