An Update on the Recent Advances and Discovery of Novel Tubulin Colchicine Binding Inhibitors

Abstract

Microtubules, formed by α- and β-tubulin heterodimer, are considered as a major target to prevent the proliferation of tumor cells. Microtubule-targeted agents have become increasingly effective anticancer drugs. However, due to the relatively sophisticated chemical structure of taxane and vinblastine, their application has faced numerous obstacles. Conversely, the structure of colchicine binding site inhibitors (CBSIs) is much easier to be modified. Moreover, CBSIs have strong antiproliferative effect on multidrug-resistant tumor cells and have become the mainstream research orientation of microtubule-targeted agents. This review focuses mainly on the recent advances of CBSIs during 2017–2022, attempts to depict their biological activities to analyze the structure–activity relationships and offers new perspectives for designing next generation of novel CBSIs.

Recognition of arylmethylidene derivatives of imidazothiazolotriazinones as novel tubulin polymerization inhibitors

“…2,3 Tubulin proteins are well-verified targets for anticancer therapy. [4][5][6][7][8][9][10] Microtubules consisting of tubulin polymers are involved in cell growth, division, motility, and intracellular transport. [10][11][12][13] Microtubule-targeting agents interfere with tubulin polymerization/depolymerization processes, disrupt the process of cell division, evoke cell cycle arrest, and eventually lead to cell apoptosis.…”

Novel Acrylate-Based Derivatives: Design, Synthesis, Antiproliferative Screening, and Docking Study as Potential Combretastatin Analogues

“…Despite the availability of different chemotherapeutic agents, no effective regimens for dealing with cancer sequences have been proposed, and the disease remains lethal and terrible. , Microtubules, including α- and β-tubulin subunits, play a critical role in numerous biological activities, including spindle formation and cellular shape maintenance. , In order to prepare the chromosomes for cell division into a pair of daughter cells, tubulin is polymerized during the cellular cycle to form microtubules. , Microtubules are an attractive target for the development of anticancer drugs due to their function in cell mitosis. , The usual tubulin inhibitor, combretastatin A-4 (CA-4) I, binds to the colchicine (Col) site, causing microtubule depolymerization and the apoptotic death of cancer cells. , For the synthesis of related compounds that may have future biological functions, CA-4 I has acted as a fundamental structural template . Numerous compounds that resemble CA-4 have been created and studied as possible anticancer drugs. − Two aromatic rings are connected by a different moiety, such as olefins, enamides, or heterocyclic functions, to form CA-4 analogues. − According to SAR studies, ring A’s trimethoxy group is a crucial pharmacophoric site for tubulin, whereas ring B’s halogenated phenyl group preserves the antitubulin activity. , The maintenance of tissue growth and homeostasis depends heavily on apoptosis, a critical cellular function. , Apoptotic pathway regulation issues have been connected to a variety of diseases, including cancer . In order to find effective cancer treatments, it has become common practice to design and prepare novel chemotherapeutic chemicals that are capable of triggering apoptotic death. − …”

“… 16 − 18 According to SAR studies, ring A’s trimethoxy group is a crucial pharmacophoric site for tubulin, whereas ring B’s halogenated phenyl group preserves the antitubulin activity. 19 , 20 The maintenance of tissue growth and homeostasis depends heavily on apoptosis, a critical cellular function. 21 , 22 Apoptotic pathway regulation issues have been connected to a variety of diseases, including cancer.…”

Novel Tetrazole Derivatives Targeting Tubulin Endowed with Antiproliferative Activity against Glioblastoma Cells

“…Unfortunately, besides the increasing efforts to develop antimitotics targeting the colchicine site, small percentages of new colchicine ligands with improved pharmacokinetic properties have been shown to maintain high antimitotic potency in the low nanomolar range exerted by CA-4 [ 42 ], thus extending the medicinal chemistry campaigns with too many cycles of drug design, synthesis, and biological evaluation [ 43 ]. To shorten and optimize the design process, in a previous work, we developed a computational screening methodology that succeeded in designing a new active molecule targeting the colchicine site.…”