Syntheses and biological evaluation of ring-C modified colchicine analogs

Abstract

Ring-C modified alkaloids were synthesized from colchicine using iminonitroso Diels-Alder reactions in a highly regio-and stereoselective fashion. Several analogs exhibited cytotoxic activity similar to that of colchicine itself against PC-3 and MCF-7 cancer cell lines, by serving as prodrugs of colchicine through retro Diels-Alder reactions under the assayed conditions. In vitro microtubule polymerization assays indicated that these modifications affected their interaction with tubulin. KeywordsColchicine; Nitroso Diels-Alder; 2-Nitrosopyridine; Cytotoxicity; Microtubule Natural (−)-(aS, 7S)-colchicine (1) (Figure 1), the major alkaloid isolated from Colchicum autumnale L. (Liliaceae), is a highly potent antimitotic agent that derives its activity by binding to protein tubulin, the basic subunit component of microtubules.1 Though its use has been limited because of its toxicity, colchicine can still be used as a lead compound for the generation of potential anticancer drugs. Thus, numerous analogs of colchicine have been synthesized in the hope of developing novel, useful drugs with more favorable pharmacological profiles. Structure-activity studies2 reveal that the trimethoxy benzene ring (A) and the methoxy tropone ring (C) of colchicine comprise the minimal structural features of the molecule needed for its high affinity binding to tubulin. One notable example is that isocolchicine (2), a colchicine analog differing only in the relative position of the methoxy and carbonyl groups of ring C, is virtually inactive and is unable to inhibit tubulin assembly.3 Ring C is also characterized by two facially differentiated 1,3-diene moieties, most suitable for cycloaddition reactions of the alkaloid.4 While Diels-Alder reactions of colchicine with several symmetrical hetero-and carbo-dienophiles have been reported,5 the biological consequence of this modification has never been disclosed, although these studies should further the understanding of the role of ring C in the development of new colchicine drugs. Our group also reported one example of hetero Diels-Alder reaction of colchicine with a pyridinylnitroso agent. 6 Encouraged by these results, we were interested to further explore the scope of this cycloaddition chemistry of colchicine. Herein we report the synthesis of a series of colchicine analogs modified at the ring C using iminonitroso Diels-Alder (NDA) reactions for modular enhancement of Nature's diversity (MEND). We also describe the results of in vitro anticancer activity of the analogs against MCF-7 and PC-3 cell lines as well as their tubulin binding affinity.Correspondence to: Marvin J. Miller. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered ...

Stereo- and regioselectivity of the hetero-Diels–Alder reaction of nitroso derivatives with conjugated dienes

“…It is a variant of the Diels–Alder reaction where either the diene or the dienophile contains a heteroatom. Hetero-Diels–Alder reactions between conjugated dienes and nitroso dienophiles affording 1,2-oxazines are utilized for the synthesis of many biologically active molecules and natural products as well as for the mild functionalization and derivatization of diene-containing natural products [1–10]. The reversibility of this reaction plays a considerable role in both the observed regio- and stereocontrol of the nitroso Diels–Alder reaction, requiring a detailed examination of the kinetic versus thermodynamic effects.…”

Cytotoxic Colchicine Alkaloids: From Plants to Drugs

“…N-substituted derivatives colchicine-lipids with different length of alkyl chain of olenyl and stearyl groups have been obtained and their interaction with lipid membrane has been studied [39]. Ring-C-modified colchicine analogs with different nitroso substituents in Diels-Alder reaction have been obtained [40].…”

Pyridine Based Antitumour Compounds Acting at the Colchicine Site

“…10), with the pyridine rings providing the adequate balance of reactivity in the cycloadditions and stability of the cycloadducts as evidenced by cytotoxic potencies similar to that of colchicine against PC-3 (prostate cancer) and MCF-7 (breast cancer) cell lines in the absence of in vitro microtubule polymerization inhibition. [67] HN…”