Regiodivergent Synthesis and Biological Activities of Indoloquinoline Based Compounds.

Cryptolepine, neocryptolepine, and isocryptolepine have remained popular synthetic targets ever since their isolation from the aqueous extracts of the West African climbing shrub Cryptolepis sanguinolenta. These natural alkaloids were found to contain significant antimalarial, antiproliferative and antimicrobial activities, making them ideal starting points for the development of novel drug candidates. As natural product synthesis is often plagued with step-heavy procedures and poor atom economy, the discovery of synthetic protocols addressing these concerns are sorely needed. In our laboratories, we have devoted our efforts into the development of regiodivergent synthesis whereby two of the indoloquinoline natural products, namely neocryptolepine and 11H-indolo[3,2-c]quinolines, could be assembled in only a few steps from a common and readily available starting material. Our synthetic endeavors to meet these goals include a cascade palladium-catalyzed Suzuki-Miyuara cross-coupling and intramolecular C-N bond formation and a photochemical nitrene insertion strategy. Furthermore, our methods also allowed for the construction of several diversely functionalized natural product derivatives which were subjected to biological evaluations.

Photodegradable antimicrobial agents: towards structure optimization.

Antibiotic resistance continues to be an ominous threat facing human health globally and urgent action is required to limit the loss of human life. The pollution of antibiotics into the environment is one of the drivers behind the crisis. With this in mind, we have developed novel photodecomposable antimicrobial agents based on an ethanolamine scaffold, which upon photoirradiation decomposes into two major inactive fragments. Herein we describe our further work on the synthesis of novel ethanolamines with a particular focus on structure activity relationship, resulting in four new active compounds which photodecomposed into inactive fragments.

Synthesis of 1,3-disubstituted bicyclo[1.1.1]pentanes by cross-coupling induced by transition metals - formation of C-C bonds.

The synthesis of 1,3-disubstituted bicyclo[1.1.1]pentanes (BCPs), by forming a C-C bond, can be achieved by cross-coupling reactions using transition metal catalysts. Two main strategies are described to access these 1,3-disubstituted BCPs, either from nucleophilic BCPs or electrophilic BCPs. Mechanisms are included where relevant.

Synthesis and Evaluation of the Tetracyclic Ring-System of Isocryptolepine and Regioiso-Mers for Antimalarial, Antiproliferative and Antimicrobial Activities.

A series of novel quinoline-based tetracyclic ring-systems were synthesized and evaluated in vitro for their antiplasmodial, antiproliferative and antimicrobial activities. The novel hydroiodide salts 10 and 21 showed the most promising antiplasmodial inhibition, with compound 10 displaying higher selectivity than the employed standards. The antiproliferative assay revealed novel pyridophenanthridine 4b to be significantly more active against human prostate cancer (IC50 = 24 nM) than Puromycin (IC50 = 270 nM) and Doxorubicin (IC50 = 830 nM), which are used for clinical treatment. Pyridocarbazoles 9 was also moderately effective against all the employed cancer cell lines and moreover showed excellent biofilm inhibition (9a: MBIC = 100 µM; 9b: MBIC = 100 µM).