Synthesis and Characterization of Griseofulvin Derivatives as Microtubule‐Stabilizing Agents

Abstract

Microtubules have been an attractive target of cancer drug discovery due to their highly dynamic nature during mitosis. Griseofulvin, a natural antifungal compound, is known to interfere with microtubule dynamics. In the present study, we prepared and analyzed twenty‐seven novel griseofulvin derivatives. Three of these compounds had GI50 values <10 μM (5.74 to 9.7 μM) in breast cancer cell line CAL‐51. The most promising compound ((2S,6’R)‐4’‐(benzhydrylamino)‐7‐chloro‐4,6‐dimethoxy‐6’‐methyl‐3H‐spiro[benzofuran‐2,1’‐cyclohexan]‐3’‐ene‐2’,3‐dione), was characterized as a microtubule‐stabilizing agent with a GI50 value of 5.74±1.43 μM compared to 10.79±3.06 μM GI50 for parental griseofulvin. It also inhibited the proliferation of other cancer cell lines, including KB‐3‐1 and HCT116, with GI50 values of 1.19±0.34 μM and 2.48±0.40 μM, respectively. Treatment of cancer cells with it resulted in aberrant mitosis causing G2/M arrest. Finally, we show that this compound increased the expression of p53 protein and induced apoptotic cell death.

Design, Synthesis, and Biological Evaluation of SSE1806, a Microtubule Destabilizer That Overcomes Multidrug Resistance

“…Microtubule targeting agents (MTAs), chemotherapeutic drugs targeting the microtubule dynamics, have been successfully used for several decades to treat various cancers. , MTAs bind free or polymerized tubulin subunits, affecting normal microtubule functions including mitotic spindle formation. This results in the failure of cells to complete mitosis, eventually leading to apoptotic cell death .…”

“…Microtubule-destabilizing agents inhibit microtubule polymerization, which disrupts the spindle microtubules, halting cell division in the metaphase. In both cases, prolonged activation of the mitotic spindle assembly checkpoint results in apoptotic cell death. , Taxanes such as paclitaxel, docetaxel, and cabazitaxel are microtubule stabilizers, while colchicine, vinblastine, and vincristine represent microtubule destabilizers. , However, despite the success, their wide-ranging clinical usage remains limited due to severe side effects and the acquisition of multidrug resistance (MDR). , MDR is responsible for the ineffectiveness of various anticancer agents and can be induced by several mechanisms; these include increased drug efflux, activation of detoxifying systems, altered DNA repair mechanisms, and evasion of drug-induced apoptosis . Therefore, over the past few decades considerable efforts have been made to develop novel MTAs that can avoid or overcome MDR.…”

“…With interest in developing new anticancer agents, ,− this study aimed to prepare a concise library of podophyllotoxin derivatives and investigate its antiproliferative potential. SSE1806 was identified as the most potent derivative and was characterized as a microtubule polymerization inhibitor that could overcome multidrug resistance.…”

“…7,8 Taxanes such as paclitaxel, docetaxel, and cabazitaxel are microtubule stabilizers, while colchicine, vinblastine, and vincristine represent microtubule destabilizers. 3,5 However, despite the success, their wide-ranging clinical usage remains limited due to severe side effects and the acquisition of multidrug resistance (MDR). 2,9 MDR is responsible for the ineffectiveness of various anticancer agents and can be induced by several mechanisms; these include increased drug efflux, activation of detoxifying systems, altered DNA repair mechanisms, and evasion of drug-induced apoptosis.…”