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Described are the studies on the mechanism of the asymmetric Biginelli reaction using proline ester salt catalyst to explain the enantioselectivity of the 3,4-dihydropyrimidin-2(1H)-one (DHPM) formation. Of the three possible activation methods by the catalyst that could provide asymmetric induction we revealed that the steric environment of the chiral enamine formed by the condensation of β-keto ester with the catalyst is most responsible for the enantioselectivity. This assumption is supported by experiments with the N-methylated catalyst, and the combination sets of L- or D-proline ester catalyst with racemic or chiral BINOL-derived phosphoric acid as counter acid. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

A series of coumarin types MMP inhibitors were designed based on gelastatin hydroxamates (1) and evaluated for TACE, cellular TNF-α, and NO inhibitory activities. Among them, compounds 9b had potent inhibitory activities in enzymatic and cellular assays and good selectivity to MMP-2 and MMP-9. Further investigation of 9b will be carried out for its efficacy in RA animal model system.

The hydroxamic acid analogues (2) of the natural product gelastatins (1) were prepared by 1 step conversion reaction. The synthetic analogues (2) showed potent enzymatic inhibitory activities against MMP-2, MMP-9, and TACE IC50's of 6, 23, and 28 nM, respectively. In addition, 2 were able to inhibit TNF-alpha production effectively in mice as well as in a macrophage cell line, RAW 264.7. The protective effect of 2 also was examined on LPS-induced acute septic shock model. The mechanism of TNF-alpha inhibition was examined by RT-PCR and Western blot analyses. The relation of TACE and alpha-secretase was examined using cellular alpha-secretase assays on IMR-32 and SH-SY5Y cell lines. The docking mode of 2 with the catalytic domain of TACE was illustrated to analyze the binding mode for the further analogue design.

The first and practical total synthesis of gelastatins 1, a novel matrix metalloproteinase inhibitor possessing antitumor activity, was accomplished in nine steps starting from Meldrum's acid.

Though it is not clear at this point whether FTase inhibition is directly related to the anticancer activity or not, development of FTI is still attractive to find a cure for cancer as well as to find the real target of these compounds. Furthermore, FTIs were also found to have great potential for treatment of malaria, African sleeping disease, and hepatitis