Anthraquinones from the roots of Morinda scabrida Craib exhibit antiproliferative activity against A549 lung cancer cells and antitubulin polymerization.

Six anthraquinones were isolated from Morinda scabrida Craib, an unexplored species of Morinda found in the tropical forest of Thailand. All six anthraquinones showed cytotoxicity against A549 lung cancer cells, with the most active compound, nordamnacanthal (MS01), exhibiting the IC50 value of 16.3 ± 2.5 µM. The cytotoxic effect was dose-dependent and led to cell morphological changes characteristic of apoptosis. In addition, flow cytometric analysis showed dose-dependent apoptosis induction and the G2/M phase cell cycle arrest, which was in agreement with the tubulin polymerization inhibitory activity of MS01. Molecular docking analysis illustrated the binding between MS01 and the α/ß-tubulin heterodimer at the colchicine binding site, and UV-visible absorption spectroscopy revealed the DNA binding capacity of MS01.

Quantitative analysis of steric effects on the regioselectivity of the Larock heteroannulation reaction.

Alkylphenylacetylene derivatives were synthesized and used as reactants in the Larock heteroannulation reaction to investigate the steric influence on regioselectivity. Large alkyl groups preferentially yielded 2-alkyl-3-phenylindole products, while smaller alkyl groups provided 3-alkyl-2-phenylindole as major products. The logarithm of regioisomeric product ratios exhibited good correlations with various steric parameters. Notably, the Charton values provided the best correlation when excluding the cyclopropyl group. In addition, the Boltzmann-weighted Sterimol parameter (wSterimol) was utilized to generate a good predictive model, indicating the B1 wSterimol as the significant regiochemical determining parameter with no obvious deviation for the cyclopropyl group. Relative atomic distances within the DFT-optimized transition state structures revealed good correlations with the logarithm of regioisomeric ratios. Furthermore, the cyclopropyl adsorption complex indicated electronic contribution, explaining the peculiar behavior of this substituent in the experimental observation.

Biphasic Dose-Dependent G0/G1 and G2/M Cell-Cycle Arrest by Synthetic 2,3-Arylpyridylindole Derivatives in A549 Lung Cancer Cells.

A collection of 2,3-arylpyridylindole derivatives were synthesized via the Larock heteroannulation and evaluated for their in vitro cytotoxic activity against A549 human lung cancer cells. Two derivatives expressed good cytotoxicity with IC50 values of 1.18±0.25 µM and 0.87±0.10 µM and inhibited tubulin polymerization in vitro, with molecular docking studies suggesting the binding modes of the compounds in the colchicine binding site. Both derivatives have biphasic cell cycle arrest effects depending on their concentrations. At a lower concentration (0.5 µM), the two compounds induced G0/G1 cell cycle arrest by activating the JNK/p53/p21 pathway. At a higher concentration (2.0 µM), the two derivatives arrested the cell cycle at the G2/M phase via Akt signaling and inhibition of tubulin polymerization. Additional cytotoxic mechanisms of the two compounds involved the decreased expression of Bcl-2 and Mcl-1 antiapoptotic proteins through inhibition of the STAT3 and Akt signaling pathways.