Synthesis and in vitro growth inhibitory activity of novel silyl- and trityl-modified nucleosides.

Seventeen silyl- and trityl-modified (5'-O- and 3',5'-di-O-) nucleosides were synthesized with the aim of investigating the in vitro antiproliferative activities of these nucleoside derivatives. A subset of the compounds was evaluated at a fixed concentration of 100µM against a small panel of tumor cell lines (HL-60, K-562, Jurkat, Caco-2 and HT-29). The entire set was also tested at varying concentrations against two human glioma lines (U373 and Hs683) to obtain GI50 values, with the best results being values of ∼25µM.

Calotroposides H-N, new cytotoxic oxypregnane oligoglycosides from the root bark of Calotropis procera.

As a part of our continuing interest in identifying anticancer drug leads from natural sources, we have investigated the n-BuOH fraction of the root bark of Calotropis procera (Ait) R. Br. Seven new oxypregnane oligoglycosides: calotroposides H-N (1-7) were isolated and identified. Their structures were established on the basis of 1D and 2D NMR studies, HRMS, and GCMS spectral data. The in vitro growth inhibitory activity of the n-BuOH fraction and compounds 1-7 was evaluated against A549 non-small cell lung cancer (NSCLC), U373 glioblastoma (GBM), and PC-3 prostate cancer cell lines. Compounds 4 and 6 showed subnanomolar growth inhibition activity with IC50 ranging from 0.5 to 0.7µM against U373 glioblastoma (GBM) and PC-3 prostate cancer cell lines. These results provide further insight into the chemical diversity and biological activities of this class of compounds.

C1,C2-ether derivatives of the Amaryllidaceae alkaloid lycorine: retention of activity of highly lipophilic analogues against cancer cells.

As a continuation of the studies aimed at the development of new anticancer agents derived from the Amaryllidaceae alkaloid lycorine, 35 C1,C2-ether analogues of this natural product were synthesized. The compounds were evaluated for antiproliferative activities in vitro in a panel of tumor cell lines with varied levels of apoptosis resistance. A strong correlation between the compound lipophilicity and anticancer activity was observed, indicating that cell permeability properties must be an important determinant in the design of lycorine-based anticancer agents. A theoretical docking model, consistent with the experimental observations, is presented.

Exploring natural product chemistry and biology with multicomponent reactions. 5. Discovery of a novel tubulin-targeting scaffold derived from the rigidin family of marine alkaloids.

We developed synthetic chemistry to access the marine alkaloid rigidins and over 40 synthetic analogues based on the 7-deazaxanthine, 7-deazaadenine, 7-deazapurine, and 7-deazahypoxanthine skeletons. Analogues based on the 7-deazahypoxanthine skeleton exhibited nanomolar potencies against cell lines representing cancers with dismal prognoses, tumor metastases, and multidrug resistant cells. Studies aimed at elucidating the mode(s) of action of the 7-deazahypoxanthines in cancer cells revealed that they inhibited in vitro tubulin polymerization and disorganized microtubules in live HeLa cells. Experiments evaluating the effects of the 7-deazahypoxanthines on the binding of [(3)H]colchicine to tubulin identified the colchicine site on tubulin as the most likely target for these compounds in cancer cells. Because many microtubule-targeting compounds are successfully used to fight cancer in the clinic, we believe the new chemical class of antitubulin agents represented by the 7-deazahypoxanthine rigidin analogues have significant potential as new anticancer agents.

Analysis of pyrrolizidine alkaloids and evaluation of some biological activities of Algerian Senecio delphinifolius (Asteraceae).

Although Senecio species are known as sources of potentially toxic pyrrolizidine alkaloids (PAs), some species of this genus are traditionally used as remedies, notably in Algeria. In this paper, the evaluation of biological activities and the analysis of PAs of Algerian specimens of Senecio delphinifolius Vahl are reported. The n-butanolic extract of the herb showed a weak antibacterial effect against Escherichia coli with a MIC of 1 mg/mL, but was inactive against Staphylococcus aureus and Pseudomonas aeruginosa. The n-butanolic extracts of the roots, stems and herb showed a modest antioxidant activity, scavenging the free radical DPPH with respective IC50 values of 55.3, 50.2 and 13.3 microg/mL. A cytotoxic effect against a series of human tumor cell lines was observed with the n-butanolic extract from stems (IC50 ranging between 34 and 88 microg/mL). The herb of the evaluated sample contains 140 ppm of PAs (senecionine, seneciphylline, integerrimine, senkirkine) and PA-related alkaloids (dehydrosenkirkine and neosenkirkine). As the major PAs belong to the toxic series (1,2-unsaturation in the pyrrolizidine cycle and macrocyclic diester), the use of S. delphinifolius should be discouraged in traditional medicine.

Antiproliferative activity of 2,3-disubstituted indoles toward apoptosis-resistant cancers cells.

Many types of cancer, including glioma, melanoma, NSCLC, among others, are resistant to apoptosis induction and poorly responsive to current therapies with propaptotic agents. We describe a series of 2,3-disubstituted indoles, which display cytostatic rather than cytotoxic effects in cancer cells, and serve as a new chemical scaffold to develop anticancer agents capable of combating apoptosis-resistant cancers associated with dismal prognoses.