Min Li Leow

Copper(II)/iron(III) co-catalyzed intermolecular diamination of alkynes: facile synthesis of imidazopyridines.

A facile synthesis of imidazo[1,2-α]pyridines has been achieved by copper(II) and iron(III) co-catalyzed C-N bond formation. This reaction involves an intermolecular oxidative diamination of alkynes with high chemoselectivity and regioselectivity.

Microwave-assisted copper(II)-catalyzed one-pot four-component synthesis of multifunctionalized dihydropyridines.

A fast and highly efficient copper-catalyzed multicomponent synthesis of 1,4-dihydropyridines under microwave irradiation is described. The protocol utilizes mild reaction conditions with low catalytic loading, leading to high yields. This methodology provides us with biologically active 1,4-dihydropyridine library for medicinal chemistry applications.

Facile access to cis-2,6-disubstituted tetrahydropyrans by palladium-catalyzed decarboxylative allylation : total syntheses of (±)-centrolobine and (+)-decytospolides A and B

cis-2,6-Tetrahydropyran is an important structural skeleton of bioactive natural products. A facile synthesis of cis-2,6-disubstituted-3,6-dihydropyrans as cis-2,6-tetrahydropyran precursors has been achieved in high regio- and stereoselectivity with high yields. This reaction involves a palladium-catalyzed decarboxylative allylation of various 3,4-dihydro-2H-pyran substrates. Extending this reaction to 1,2-unsaturated carbohydrates allowed the achievement of challenging β-C-glycosylation. Based on this methodology, the total syntheses of (±)-centrolobine and (+)-decytospolides A and B were achieved in concise steps and overall high yields.

[3 + 2] Cycloaddition on Carbohydrate Templates: Stereoselective Synthesis of Pyrrolidines

Pyrrolidine derivatives were prepared in high diastereoselectivities and good yields via a [3 + 2] cycloaddition of a tert-butyldimethylsilyl protected carbohydrate-based allene with a diverse range of imines. The subsequent removal of the carbohydrate auxiliary afforded a variety of pyrrolidines with excellent enantioselectivities (up to 99% ee). Selective reduction of the pyrrolidines further demonstrated the potential of this strategy.

Directed orthometalation and the asymmetric total synthesis of N-deoxymilitarinone A and torrubiellone B.

A diverted total synthesis (DTS) approach to the total synthesis of pyridone alkaloids N-deoxymilitarinone A (8) and torrubiellone B (10) has been developed. The common intermediate 14 was first assembled by a dual directed orthometalation process using a methoxymethyl group as directed metalation group. Other crucial steps include the assembly of polyenes under aldol condensation for DTS using general and concise strategy and diastereoselective synthesis of the syn-dimethyl array by an Evans aldol reaction.

Adamantyl Derivative As a Potent Inhibitor of Plasmodium FK506 Binding Protein 35

FKBP35, FK506 binding protein family member, in Plasmodium species displays a canonical peptidyl-prolyl isomerase (PPIase) activity and is intricately involved in the protein folding process. Inhibition of PfFKBP35 by FK506 or its analogues were shown to interfere with the in vitro growth of Plasmodium falciparum. In this study, we have synthesized adamantyl derivatives, Supradamal (SRA/4a) and its analogues SRA1/4b and SRA2/4c, which demonstrate submicromolar inhibition of Plasmodium falciparum FK506 binding domain 35 (FKBD35) PPIase activity. SRA and its analogues not only inhibit the in vitro growth of Plasmodium falciparum 3D7 strain but also show stage specific activity by inhibiting the trophozoite stage of the parasite. SRA/4a also inhibits the Plasmodium vivax FKBD35 PPIase activity and our crystal structure of PvFKBD35 in complex with the SRA provides structural insights in achieving selective inhibition against Plasmodium FKBPs.

Collective synthesis of 4-hydroxy-2-pyridone alkaloids and their antiproliferation activities.

A collective synthesis of 4-hydroxy-2-pyridone alkaloids--specifically, pretenellin B, prebassianin B, farinosone A, militarione D, pyridovericin, and torrubiellone C--has been achieved. Key steps include using a strategic convergent method to synthesize the densely substituted pyridone key intermediate by Suzuki-Miyaura cross-coupling reaction, a divergent synthesis approach of target molecules by aldol condensation of pyridone intermediate with homologous aldehydes, and an iterative synthesis of homologous aldehydes with all-trans-polyene backbones. Interestingly, among the six tumor cell lines investigated, torrubiellone C was found to induce potent and apoptotic inhibitory activities on Jurkat T cells with IC50 values of 7.05 μM. Hence, this approach could potentially contribute to the synthesis of bioactive small-molecule libraries as well as drug discovery.

Benzofuran-Based Estrogen Receptor α Modulators as Anti-Cancer Therapeutics: In Silico and Experimental Studies

In the search for new estrogen receptor alpha (ERα) modulators, a trial molecular screening was conducted and 5,6-dihydroxybenzofuran was identified as a possible drug target for ERα. The target molecular modelling molecule 1 and a series of 5,6-dihydroxybenzofurans have been synthesized and evaluated for their anti-proliferation activities against MCF-7 and MDA-MB-231 cells. From the SAR studies, potential functional groups have been identified, the two hydroxyl groups at C-5 and C-6 and the phenyl ring at C-2, which showed considerable cytotoxicity in MCF-7 breast cancer cells. In addition, the apoptotic abilities of the compounds have been measured in both MCF-7 ER(+) and MDA-MB-231 ER(-) breast cancer cells. The results demonstrated that our compounds inhibit MCF-7 breast cancer cells via ER(+). These preliminary results provide valuable information towards the identification of important functional groups present on 5,6-dihydroxybenzofuran, which could be a promising scaffold for designing novel ER ligands.