Synthetic Strategy toward the Pentacyclic Core of Melodinus Alkaloids.

The three-component Povarov reaction is efficiently utilized for construction of the pentacyclic framework of complex Melodinus alkaloids, which is amenable to expansion to other complex natural products. The key steps were Povarov reaction, one-pot reductive cyclization, and ring-closing metathesis (RCM) reaction.

Synthesis of imidazo-thiadiazole linked indolinone conjugates and evaluated their microtubule network disrupting and apoptosis inducing ability.

A series of imidazo[2,1-b][1,3,4]thiadiazole linked indolinone conjugates were synthesized and investigated for antiproliferative activity in different human cancer cell lines by changing various substitutions at indolinone and phenyl ring systems. Among them conjugates 7, 14 and 15 were exhibited potent antiproliferative activity with GI50 values from 0.13 to 3.8 µΜ and evaluated for cell cycle analysis, tubulin polymerization assay and apoptosis. Treatment with 7, 14 and 15 were resulted in accumulation of cells in G2/M phase, inhibition of tubulin assembly, disruption of microtubule network. Inhibition of tubulin polymerization was further supported by Western blot analysis. In addition, the conjugates (7, 14 and 15) also showed apoptosis in HeLa cell line, detailed biological studies such as Hoechst 33,258 staining, DNA fragmentation and caspase-3 assays suggested that these compounds induce cell death by apoptosis. Docking studies revealed that these compounds (7, 14 and 15) bind with αAsn101, αThr179, αSer178, ßCys241, ßLys254 and ßLys352 in the colchicine-binding site of the tubulin.

Synthesis, structural studies, and cytotoxic evaluation of novel ursolic acid hybrids with capabilities to arrest breast cancer cells in mitosis.

Some novel chemically modified frameworks of ursolic acid have been designed and synthesized. The key step was the cycloaddition of azidopropyl-3ß-hydroxy-urs-12-en-28-oate with the appropriate C28 propargyl esters of ursolic, corosolic, asiatic, oleanolic, and betulinic acid under Click reaction conditions, and the products were obtained in 74-84% yields. In view of their intriguing structural diversity, they have been subjected to detailed 1D and 2D NMR studies and their structures are thoroughly assigned. The synthesized compounds were screened for their anticancer potential against two human breast cancer cell lines (MCF-7 & MDA-MB-231) using sulforhodamine B cell proliferation assay. The GI50 data revealed that the synthesized compounds exhibit highly potent activities against the two tested cell lines. Interestingly, the synthesized compounds showed selectivity and higher activity against MDA-MB-231 cell line than MCF-7. Among the tested compounds, compound 17 is the most potent one with GI50 value of 1.4 ± 0.1 µM and showed 2.9 times more activity than the standard doxorubicin against MDA-MB-231. In addition, 17 arrests cells in mitotic phase of cell cycle, resulting in a change in cell phenotype. In view of the selective and highly promising activity against breast cancer cell lines, these compounds can serve as promising leads for further development.