Imidazo[2,1-b]thiazole-Coupled Natural Noscapine Derivatives as Anticancer Agents

Abstract

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.

Thiazole Ring—A Biologically Active Scaffold

“…Kantevari et al [131] reported the synthesis of a series of imidazo[2,1-b]thiazolecoupled noscapine derivatives 85a-o and 85a-o (Figure 33) and their in vitro cytotoxicity screening against four tumor cell lines: DU-145 (prostate), MCF-7 (breast), SK-N-SH (neuroblastoma), and MIAPaCa-2 (pancreatic), by SRB assay. The screening revealed that among the tested compounds 85a, 86b, 86c, 86e, and 86o were found to be active against all tested cancer cells.…”

Bioengineering of Anti‐Inflammatory Natural Products

“…The biosynthesis of noscapine ( 5 ) starts from l ‐tyrosine ( 6 ) and proceeds via the intermediate reticuline ( 7 ). Residues that were successfully modified in reticuline and noscapine by biotechnological or semisynthetic methods are highlighted [90–102,105,106,108] …”

“…In the past 10 years, several attempts have been made to generate noscapine analogues with favorable properties. [91][92][93][94][95][96][97][98][99][100][101][102] As a consequence of the complex stereochemistry, total chemical syntheses of noscapinoids are hard to realize. Therefore, semisynthesis has become the method of choice.…”

“…Residues that were successfully modified in reticuline and noscapine by biotechnological or semisynthetic methods are highlighted. [90][91][92][93][94][95][96][97][98][99][100][101][102]105,106,108] The biotechnological production of noscapine analogues became possible following the discovery and characterization of its biosynthesis gene cluster in the opium poppy. [103,104] The natural assembly of 5 is extremely complex.…”

Synthesis, the antiexudative and antimicrobial activity of 6-arylidene substituted imidazo[2,1-b]thiazoles

“…Імідазо [2,1-b]тіазольне ядро є, зокрема, структурним фрагментом алостеричного модулятора рецепторів γ-аміномасляної кислоти (GABA A R) [2], анксіолітичного агента WAY-181187 (SAX-187) [3], модуляторa сиртуїну [4] та модуляторів білка CXCR4, які специфічно націлені на його мінорну кишеню [5] (рис.). Окрім цього, серед похідних імідазо [2,1-b]тіазолу виявлено сполуки з вираженою антимікробною [6,7], нейропротекторною [8], протираковою [9][10][11][12] активностями, а також інгібітори 15-ліпоксигенази [13] й індоламін-2,3-діоксигенази [14]. До ряду гідрованих імідазо [2,1-b]тіазолів належить левамізол -антигельмінтний та імуностимулювальний засіб, що дотепер використовують у терапевтичній практиці [15].…”