Discovery of Novel, Selective, and Nonbasic Agonists for the Kappa-Opioid Receptor Determined by Salvinorin A-Based Virtual Screening.

Modulating the kappa-opioid receptor (KOR) is a promising strategy for treating various human diseases. KOR agonists show potential for treating pain, pruritus, and epilepsy, while KOR antagonists show potential for treating depression, anxiety, and addiction. The diterpenoid Salvinorin A (SalA), a secondary metabolite of Salvia divinorum, is a potent and selective KOR agonist. Unlike typical opioids, SalA lacks a basic nitrogen, which encouraged us to search for nonbasic KOR ligands. Through structure-based virtual screening using 3D pharmacophore models based on the binding mode of SalA, we identified novel, nonbasic, potent, and selective KOR agonists. In vitro studies confirmed two virtual hits, SalA-VS-07 and SalA-VS-08, as highly selective for the KOR and showing G protein-biased KOR agonist activity. Both KOR ligands share a novel spiro-moiety and a nonbasic scaffold. Our findings provide novel starting points for developing therapeutics aimed at treating pain and other conditions in which KOR is a central player.

Structure-activity relationship study to improve cytotoxicity and selectivity of lonafarnib against breast cancer cells.

Lonafarnib is designed as a farnesyltransferase (FTase) inhibitor and displays inhibitory activities against a wide range of tumor cells. However, a major disadvantage is its unselective activity and high cytotoxicity against nonmalignant cells. Therefore, we structurally modified the terminal 4-methylpiperidine-1-carboxamide residue of lonafarnib and evaluated the antiproliferative effects of the resulting derivatives in Michigan Cancer Foundation - 7 (MCF-7) breast cancer cells as well as simian virus 80 (SV-80) fibroblasts. The highest cytotoxicity against both cell lines (IC50 about 2 µM) was shown by the piperidin-4-yl carbamate 15i and the S-(piperidin-4-yl) carbamothioate 15j. Selectivity for tumor cells was realized in the case of the 1-cyclohexyl-1-methylurea derivative 15b. It reduced the growth of MCF-7 cells with an IC50 of 11.4 µM (lonafarnib: IC50 = 10.8 µM) without influence on the growth of SV-80 cells (IC50 > 50 µM; lonafarnib: IC50 = 14.0 µM). Molecular modeling studies were performed to correlate the cytotoxicity with possible FTase interactions. The theoretical investigations, however, documented a comparable attachment of active, less active, and inactive compounds and did not allow an interpretation of the biological results based on these theoretical considerations.

Velucarpin D, a new pterocarpan from the stems of Dalbergia velutina and its cytotoxicity.

A new pterocarpan, named velucarpin D (1), along with nine known pterocarpans (2-10) were isolated from the stems of Dalbergia velutina. Their structures were determined by spectroscopic analysis. All isolated compounds were evaluated for their cytotoxicity against five human cancer cell lines (KB, HeLa S-3, MCF-7, Hep G2, and HT-29). Compound 2 showed potent cytotoxicity against all the five human cancer cell lines with IC50 values in the range of 4.74-8.46 µM. In addition, compounds 1, 3, 4, 5 and 9 showed moderate cytotoxicity against both KB and HeLa S-3 cells with IC50 values in the range of 14.23-29.35 µM.

Chemical constituents and derivatization of melodorinol from the roots of Melodorum fruticosum.

Chemical investigation of the CH2Cl2 and MeOH crude extracts of the roots of Melodorum fruticosum Lour. led to the isolation of 15 known compounds, of which 5, 10, and 12-15 are reported for the first time from this plant. In addition, melodorinol (7) was derivatized to afford six new (7a-7d and 7f-7g) analogues and one known compound (7e). Their structures were identified on the basic of spectroscopic data Most of them were evaluated for their cytotoxicity against KB, HeLa, MCF-7 and HepG-2 cell lines. Compounds 4 and 7b were the most potent to all cell lines.