Indolizine-phenothiazine hybrids as the first dual inhibitors of tubulin polymerization and farnesyltransferase with synergistic antitumor activity

Recent Progress on Tubulin Inhibitors with Dual Targeting Capabilities for Cancer Therapy

“…The dual tubulin−farnesyltransferase (FTase) inhibitor 74 (Figure 17C) was discovered through hybridizing indolizine and phenothiazine. 164 Compound 74 displayed remarkable tubulin polymerization and FTase inhibition with IC 50 values of 1.11 and 0.39 μM, respectively. The SARs indicated that the unsubstituted nitrogen atom of phenothiazine of compound 74 is important for tubulin polymerization inhibition, and the small substituted groups of indolizine are tolerated for FTase inhibition.…”

“…The dual tubulin–farnesyltransferase (FTase) inhibitor 74 (Figure C) was discovered through hybridizing indolizine and phenothiazine . Compound 74 displayed remarkable tubulin polymerization and FTase inhibition with IC 50 values of 1.11 and 0.39 μM, respectively.…”

Development of Phenothiazine Hybrids with Potential Medicinal Interest: A Review

“…The phenothiazine system was unsubstituted on the nitrogen atom and the presence of indolizine bearing methyl or methoxy substituents are important for this activity. The authors highlighted that even though compound 10a is not the best dual inhibitor of tubulin polymerization and FTase, its potent effect in cancer cells lines suggests that this hybrid can more effectively penetrate the cell membrane, eventually reaching other biological targets [ 33 ].…”

Switching the reactivity of cyanomethylpyridinium salts in the 1,3-cycloaddition conditions with alkyl propiolates to cyanoindolizines or cyanoazaindolizinyl-indolizines

“…8 Our group recently discovered 3-acetylindolizine derivative H with excellent potential to inhibit the cell growth of cancer cell lines, especially MDA-MB-435 melanoma cells (GI50 = 1.8 nM). 9 In an endeavor to enrich the structure-activity relationships information in this series and to provide additional insights into their anticancer potential, we were interested in the synthesis of a portfolio of compounds bearing a cyano group in position 3 of the indolizine as a withdrawing isostere of the acetyl unit (Figure 1). The new study mainly focused on the synthesis of key intermediates 3-cyanoindolizines 3 (target compounds, Figure 1), essential for a future access to the designed phenothiazine-indolizine hybrids.…”

“…A straightforward synthetic pathway was developed which allowed to tune the reactivity and obtain either classical cyanoindolizines or the cyanoazaindolizinyl-indolizines. [1][2][3][4][5][6][7][8] indolizine H 9 and of target and unexpected compounds investigated in this study.…”