A novel anti-cancer role of ß-apopicropodophyllin against non-small cell lung cancer cells.

We previously reported that podophyllotoxin acetate (PA) inhibits the growth and proliferation of non-small cell lung cancer (NSCLC) cells and also makes them more sensitive to radiation and chemotherapeutic agents. In an attempt to enhance PA activity, we synthesized 34 derivatives based on podophyllotoxin (PPT). Screening of the derivative compounds for anti-cancer activity against NSCLC led to the identification of ß-apopicropodophyllin (APP) as a strong anti-cancer agent. In addition to its role as an immunosuppressive regulator of the T-cell mediated immune response, the compound additionally showed anti-cancer activity against A549, NCI-H1299 and NCI-460 cell lines with IC50 values of 16.9, 13.1 and 17.1 nM, respectively. The intracellular mechanisms underlying the effects of APP were additionally examined. APP treatment caused disruption of microtubule polymerization and DNA damage, which led to cell cycle arrest, as evident from accumulation of phospho-CHK2, p21, and phospho-Cdc2. Moreover, APP stimulated the pro-apoptotic ER stress signaling pathway, indicated by elevated levels of BiP, phospho-PERK, phospho-eIF2α, CHOP and ATF4. We further observed activation of caspase-3, -8 and -9, providing evidence that both intrinsic and extrinsic apoptotic pathways were triggered. In vivo, APP inhibited tumor growth of NSCLC xenografts in nude mice by promoting apoptosis. Our results collectively support a novel role of APP as an anticancer agent that evokes apoptosis by inducing microtubule disruption, DNA damage, cell cycle arrest and ER stress.

Total Synthesis of the Claimed Structure of (±)-Hyptinin and Structural Revision of Natural Hyptinin.

A total synthesis of (±)-hyptinin was achieved via a convergent route using the key phosphonate, cyclic ketone, and aryl Grignard components. The 1H and 13C NMR spectra of natural hyptinin did not agree with those of the synthesized compound. In particular, there were considerable differences between the signals assigned to the protons and carbons surrounding the lactone carbonyl group for the natural and synthesized compounds. The NMR data strongly suggested that the naturally occurring compound, hyptinin, was a structural isomer of the synthesized compound. The structure of the natural compound was eventually established as (+)-ß-apopicropodophyllin, based on the synthesis results.

Stereoselective reactions. XVIII. Synthesis and cytotoxicity of the demethyl derivatives of steganes.

Demethyl derivatives of steganes and deoxypodorhizon, 3, 4, 6, 7, 9, 10, 12, 13, 18, 23, were prepared by the selective demethylation of the methoxy group of steganes and deoxypodorhizon, 2, 5, 8, 11, 22. The cytotoxicity of these derivatives was evaluated against KB cell and was found not to exceed that of the parent steganes. 4-Demethyldeoxypodorhizon (18) was found to show more potent cytotoxicity than deoxypodorhizon.