Our interests in alkaloids have drawn our attention to devising and refining synthetic routes toward many of their classes. As an ongoing part of our programme, we continue to seek new synthetic methods for the benzazepine moiety, which occurs frequently in both natural products and synthetic drugs. Some benzazepines have been shown to bind to the dopaminergic family of G-protein coupled receptors, which have been implicated in certain diseases of the nervous system such as Alzheimer’s and dementia. Trepipam is a benzazepine-containing drug used as a tranquilizer.

     Since pyrroles are an important core of some bioactive marine natural products, their syntheses have been contemplated. Our interests in this area have been to develop general synthetic methods for 3,4-diaryl pyrroles, as they are the common subunit in marine natural products known as lamellarins, ningalins, purpurones, and lukianols. Lamellarins have been shown to exhibit cytotoxicity, inhibit cell division, exhibit immunomodulatory activity, inhibit HIV-1 integrase, and, more importantly, reverse multidrug-resistance in some cancer cell lines. Some lamellarins have been evaluated for their toxicity and investigated for their molecular mode(s) of biological activities. Since they are related biosynthetically to the lamellarins, ningalins and lukianols are expected to possess some similar activities. Despite the existing synthesis of pyrroles, in general, synthetic methods for 3,4-diaryl pyrroles have been scarce. We have successfully developed novel synthesis of both symmetric and asymmetric 3,4-diaryl pyrroles. In addition, we continue to make progress on the synthesis of lamellarins from readily available starting materials and by high-yielding reaction sequences. Ningalin C, one of the more complex marine natural products, was successfully synthesized in only a few chemical operations.

     Sharing some structural similarities to lamellarins, but not as alkaloids, combretastatins have been shown to possess significant anti-cancer property. In fact, some combretastatins are in the clinical phase of drug development in different parts of the world. Currently, orphan drug status has been granted by the U.S. FDA for combretastatin A4 prodrug produced by OxiGene Company in the treatment of multiple forms of thyroid cancers – anaplastic, medullary, stage IV papillary and stage IV follicular. Our effort in this area includes developing new synthetic methods for the combretastatin framework and exploring new analogs with potentially better biological and pharmacological parameters against various cancer cell lines.

     Besides these aforementioned classes of alkaloids, our interests include synthetic studies of indoloquinoline (e.g., cryptolepine), isoquinonaphthyridine, indolopyrido-naphthyridine, isoquinoline, benzophenanthridine, benzoquinolizine, protoberberine, aporphine, erythrina, and other related alkaloids. These alkaloids exhibit therapeutic potential and some have been used clinically. Cryptolepine, for example, is a potent antiplasmodial agent. Glaucine, an aporphine, exhibits anti-tussive activity in humans comparable to that of codeine but, unlike codeine, is non-narcotic. Erysotrine, an erythrina alkaloid, has been shown to exhibit properties consistent with those of a competitive neuromuscular blocking agent and the compound, as found in nature in the leaf and bark of E. superosa, may be responsible for the observed anti-tumor activity associated with the extract. Some members of protoberberine alkaloids have been reported to exhibit several types of biological activities such as anti-leukemic, anti-tumor, and anti-inflammatory activities. Similarly, some indolopyridonaphthyridines display anti-proliferative and anti-leukemic activities.

     As malaria continues to be a major public health threat in Thailand, new drugs to battle this deadly disease are still much in need. Our continuing interest in this area has prompted us to consider mefloquine, a quinoline alkaloid, as a candidate for further development since the parent drug has already been used. However, structural modifications are necessary since drug resistance, even against mefloquine, has been encountered in some parts of Thailand. Our programme has devoted effort into developing some alternative approaches for the synthesis of the key intermediates, not only for mefloquine itself, but also for its derivatives. Our aim is to incorporate flexibility in our synthetic routes to allow for an easy access to a large number of structurally diverse analogs for further anti-malarial evaluation.

     Solid phase synthesis is a relatively new area in which we are involved. Unlike classical approaches in organic synthesis, solid phase synthesis offers some significant advantages. As solid-supported reagents, they offer crucial applications in “green chemistry” as these reactions employing solid-supported reagents need less solvent and require no additional step involving water to separate organic and aqueous materials, thus producing less waste. As solid-supported substrates, they offer a number of advantages in that a greater number of reactions can be performed sequentially with no purification of the intermediates. The excess reagents from each step can be recycled through the synthetic plans, making this approach more economical than the classical ones. Applications of solid phase synthesis for various alkaloids such as lamellarins and isoquinolines are being extensively investigated.

     Our research has recently been extended into the area of mechanism-based biological investigations. The initial project will focus on the potential anti-cancer properties of lamellarins, which have been shown to exert these effects by inhibiting the topoisomerase I enzyme. Lamellarins will be evaluated for their cytotoxicity against various cancer cell lines, as well as their inhibitory effects on the purified topoisomerase I in vitro. Structure-activity relationship (SAR) studies will then be carried out in order to simplify the structures to include only the parts essential to exert biological activities, as well as to design novel analogs of the existing parent compounds to achieve more desirable biological, pharmacological, and toxicological properties. Some of the most active compounds will be selected for further development into new anti-cancer agents.

     Apart from experimental research, computational chemistry has exerted its impact on modern drug design and discovery. Following the identification of drug targets, in silico screening of potential and diverse chemical structures have been employed to obtain structurally optimized lead compounds for synthesis, as well as in vitro and in vivo biological evaluations. The role of molecular modeling in drug design has been extended to establish quantitative structure-activity relationship (QSAR) even for those families of compounds with yet unidentified molecular targets. This line of research provides another dimension in designing new bioactive compounds with desirable biological, pharmacological, and toxicological properties more efficiently and effectively.

     Laboratory of Medicinal Chemistry is working in collaboration, outside the Institute, with Mahidol University (Research and Development of Synthetic Drugs Program, Institute of Science and Technology for Research and Development, Faculty of Pharmacy, and Faculty of Science), Srinakharinwirot University (Faculty of Science and Faculty of Medicine), and Kasetsart University (Faculty of Science).

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