ThaiREU in Organic Chemistry

Research Project Descriptions

Dr. Somsak Ruchirawat Chulabhorn Research Institute

In medicinal chemistry, we are interested in the synthesis of biologically active compounds, especially nitrogen heterocycles. Current target areas include anti-malarial compounds, isoquinolines and the lamellarin series of natural products. A student might be involved in the synthesis of analogs, using our already developed synthetic route, for subsequent in-house biological screening.

In natural products chemistry, our emphasis is on the extraction of active natural products from indigenous Thai plants. The work involves extraction, isolation, structural elucidation (principally by NMR methods), and biological evaluation.

Dr. Poonsakdi Ploypradith Chulabhorn Research Institute

Our research program involves both the target-based and methodology-driven total synthesis of natural products for drug discovery. Our main objective is to develop efficient synthetic routes toward natural products ranging from chromans to pyrroloisoquinoline lactones. While natural products are an important source of medicinally and therapeutically useful scaffolds for drug discovery, the low natural abundance of biologically active compounds are the major limitation for extensive investigation. Through total synthesis, these compounds can be prepared in sufficient quantities for establishing structure-activity relationships (SARs), detailed investigation of the therapeutic indices, and for further incorporation of pharmacologically useful functional groups to provide the appropriate biological profile for drug development. Studies on their mechanisms of action also provide very useful information for developing more desirable analogues.

Our research group has been interested in lamellarins, which are a group of marine natural products. A number of successful synthetic routes have been developed in our group including the use of environmentally friendly solid-supported reagents. Thus far, over 60 structurally related analogues of lamellarins have been successfully prepared in our laboratory and preliminary SARs have been established. Currently, our effort has been focused on streamlining the structural requirements of lamellarins while incorporating functional groups to enhance aqueous solubility and lower toxicity toward normal cells.

We have also developed a new synthetic methodology to prepare 2-arylchromans via the intermediacy of the highly reactive species ortho-quinone methide (o-QM). The method provides products in good to excellent yields and moderate to excellent diastereoselectivities. Our involvement in this methodology-driven total synthesis emphasizes the generation of o-QMs under mild conditions using either (1) p-TsOH immobilized on silica (PTS-Si) or (2) transition metal salts (e.g. Pt(IV) or Au(III)). Once generated, the formal [4+2]-cycloaddition reactions are investigated with a variety of appropriately activated alkenes acting as dienophiles. Both intermolecular and intramolecular modes of cyclization reactions have been studied to provide the corresponding chromans, some of which are structurally related to natural products with a wide range of biological activities.

Selected Recent Publications:

1) Tummatorn, J.; Ruchirawat, S.; Ploypradith, P. A Convergent General Strategy for the Functionalized 2-Aryl Cycloalkyl-fused Chromans: Intramolecular Hetero Diels—Alder (HDA) Reactions of ortho-Quinone Methides (o-QMs). Chem. Eur. J. 2010, 16, 1445-1448.

2) Chittchang, C.; Gleeson, M. P.; Ploypradith, P.; Ruchirawat, S. Assessing the Drug-likeness of Lamellarins, a Marine Derived Natural Product Class with Diverse Oncological Activities. Eur. J. Med. Chem. 2010, 45, 2165-2172.

3) Batsomboon, P.; Phakhodee, W.; Ruchirawat, S.; Ploypradith, P. Generation of ortho-Quinone Methides by p-TsOH on Silica and Their Hetero-Diels—Alder Reactions with Styrenes. J. Org. Chem. 2009, 74, 4009-4012.

4) Tangdenpaisal, K.; Sualek, S.; Ruchirawat, S.; Ploypradith, P. Factors Affecting Orthogonality in the Deprotection of 2,4-Di-Protected Aromatic Ethers Employing Solid-Supported Acids. Tetrahedron 2009, 65, 4316-4325.

5) Chittchang, M.; Batsomboon, P.; Ruchirawat, S.; Ploypradith, P. Cytotoxicities and Structure-Activity Relationships of Natural and Unnatural Lamellarins towards Cancer Cell Lines. ChemMedChem 2009, 4, 457-465.

6) Baunbæk, D.; Trinkler, N.; Ferandin, Y.; Lozach, O.; Ploypradith, P.; Ruchirawat, S.; Ishibashi, F.; Iwao, M.; Meijer, L. Anticancer Alkaloid Lamellarins Inhibit Protein Kinases. Mar. Drugs 2008, 6, 514-527.

Dr. Thawatchai Tuntulani Chulalongkorn University

Dr. Thawatchai Tuntulani is the coordinator of the Supramolecular Chemistry Laboratory (SML), Department of Chemistry, Faculty of Science, at Chulalongkorn University. Dr. Tuntulani’s research is focused on the synthesis of electrochemical heteroditopic anion sensors containing crown ethers or calix[4]arenes as cation binding sites and amidoferrocene as anion binding sites. The binding and detection abilities of these anion sensors in the absence and presence of alkali metal ions is then investigated by NMR, cyclic voltammetry and square wave voltammetry.

Students will prepare novel anion sensors using the synthetic route developed in this lab, characterize their products by 1H-NMR, 13C-NMR, elemental analysis and X-ray crystallography, and then investigate the anion binding abilities.

Dr. Palangpon Kongsaeree Mahidol University

Dr. Kongsaeree’s lab is interested in developing new effective treatments against malaria by investigating antifolate drugs such as pyrimethamine, which inhibit dihydrofolate reductase enzyme (DHFR) at the cellular level. Structural investigation of dihydrofolate reductase-thymidylate synthase has been explored in this laboratory: the recombinant gene was cloned, the enzyme was expressed and purified to homogeneity, and the enzyme in complex with pyrimethamine was crystallized. The X-ray structure revealed the binding mechanism of the drug with atomic details. Current work is focused on elucidating the drug-resistance mechanism by studying crystal structures of mutant enzymes complexed with antifolates, leading to the development of a new generation of antifolate inhibitors.

Concurrently, new leads for antimalarials are being explored by searching for bioactive compounds from microorganisms, especially fungi from tropical Thailand. Fungi with promising bioactivity profiles in a preliminary screening stage will be cultured and then using bioassay-guided isolation, pure secondary metabolites will be obtained using chromatographic techniques including HPLC. The chemical identity of each compound will be established spectroscopically using NMR, IR, MS, X-ray crystallographic analysis when possible. ThaiREU students can take part in work with mutant enzymes, or in bioassay-guided natural product isolation and structural elucidation.

Dr. Thientong Thongpanchang Mahidol University

Dr. Thongpanchang’s research focus is in three main categories: 1) the development of new synthetic methodologies towards compounds with interesting activities, 2) the design and development of new materials and 3) physical organic chemistry in terms of the relationship between molecular conformations and properties. He is now studying the synthesis of arylsulfides by the addition of nucleophiles to the keto tautomer of phenol in the presence of acid. A variety of arylsulfides can be prepared in large quantity, as well as aryldioxins and aryldithiins, which are important pharmacophores with possible new electro- and optochemical materials. He is also interested in preparing highly conjugated helicenes for new material applications using an acid catalyzed intramolecular cyclization of binaphthols, or by photocyclization of diarylsulfides. A variety of helicenes with key functional groups will be prepared; incorporation into macromolecules by supramolecular assembly or via polymerization will provide materials with interesting properties.
He is also interested in establishing the relationship between the conformation of bonds and the properties of the molecules, especially as it applies to the process of resolution. With camphanate ester derivatives of binaphthols as model compounds, each diastereomerically pure material can be isolated. Conformation analysis by means of CD / ORD and NMR spectroscopy complemented with molecular conformation calculations as well as X-ray analyses provides an insight into chemical bonding leading to the difference in polarity of each diatereomeric pair on TLC. This finding can lead to an efficient yet most straightforward method for the determination of the absolute configuration of binaphthols.

Dr. Tirayut Vilaivan Chulalongkorn University

Dr. Vilaivan's main research interest concerns a new class of DNA mimic with a peptide-like backbone called "Peptide Nucleic Acid" (PNA). During the past ten years, he has designed and synthesized a number of PNA systems based on a conformationally rigid proline skeleton. Some of these PNA structures show unique nucleic acid binding properties such as exceptionally high affinity and specificity towards DNA, high preference for antiparallel binding mode, and selective recognition between DNA and RNA. Work in this area is directed towards better understanding the structural aspects of the binding and designing new PNA systems with enhanced binding properties. Their potential applications in diagnostics and therapeutics are current subjects of intensive research.

Dr. Vilaivan's two other major research areas are 1) development of new catalysts for asymmetric nucleophilic addition to C=N, C=O and C=C bonds, and 2) synthetic Dihydrofolate Reductase Inhibitors to be used as antimalarial drugs effective against mutant strains of maleria.

For more details please visit: http://www.chemistry.sc.chula.ac.th/personnel/details/vilaivan.htm

Representative publications:
1. Vilaivan, T.; Srisuwannaket, C. "Hybridization of pyrrolidinyl peptide nucleic acids and DNA: Selectivity, base-pairing specificity, and direction of binding" Org. Lett. 2006 , 8 , 1897-1900.
2. 2. Vilaivan, T.; Bhanthumnavin, W.; Sritana-Anant, Y. "Recent advances in catalytic asymmetric addition to imines and related C=N systems" Curr. Org. Chem. 2005 , 9 , 1315-1392.
3. . Vilaivan, T.; Winotapan, C.; Banphavichit, V.; Shinada, T.; Ohfune, Y. " Indium-mediated asymmetric Barbier-type allylation of aldimines in alcoholic solvents: Synthesis of optically active homoallylic amines" J. Org. Chem. 2005 , 70 (9), 3464-3471.
4. . Banphavichit, V.; Mansawat, W.; Bhanthumnavin, W.; Vilaivan, T. "A highly enantioselective Strecker reaction catalyzed by titanium- N -salicyl- b-amino alcohol complexes" Tetrahedron 2004 , 60 , 10559-10568 .
5. Vilaivan, T.;   Saesaengseerung, N.; Jarprung, D; Kamchonwongpaisan, S.; Sirawaraporn, W.; Yuthavong, Y. "Synthesis of solution-phase combinatorial library of 4,6-diamino-1,2-dihydro-1,3,5-triazine and identification of new leads against A16V+S108T mutant dihydrofolate reductase of Plasmodium falciparum " Bioorg. Med. Chem. 2003 , 11 , 217-224.

6. . Vilaivan, T.; Lowe, G. "A novel pyrrolidinyl PNA showing high sequence specificity and preferential binding to DNA over RNA" J. Am. Chem. Soc. 2002 , 124 , 9326-9327 .

Dr. Charnsak Thongsornkleeb Chulabhorn Research Institute

Dr. Nopporn Thasana Chulabhorn Research Institute

Dr. Thasana's research interests: Microwave-assisted organic synthesis, Organometallic chemistry, Solid-phase synthesis, Green chemistry, Synthesis of bioactive natural products

Research in Dr. Thasana’s lab focuses on the synthesis of bioactive lactones and lactams. The synthesis of various natural alkaloids and their analogues will be studied using Cu(I)-mediated microwave(MW)-assisted C-O and C-N bond formation (Figure 1). Students will study the Cu(I)-meditaed/MW-assisted coupling under “subcritical water” conditions as Green Chemistry developed in this lab.

Figure 1. Syntheses of bioactive lactone and lactam derivatives

In addition, the lab is also interested in organometallic chemistry, particularly the use of organolithiums used in the synthesis of unsymmetrical benzils as applied to the synthesis of bioactive molecules:

Figure 2. Synthesis of unsymmetrical benzil derivatives

Selected Recent Publications:

1) Thasana, N.; Prapagdee, B.; Rangkadilok, N.; Sallabhan, R.; Lwin Aye, S.; Ruchirawat, S.; Loprasert, S. Bacillus subtilis SSE4 produces subtulene A, a new lipopeptide possessing an unusual C15 unsaturated β−amino acid. FEBS Lett. 2010, 584, 3209-3214.
2) Boonya-udtayan, S.; Yotapan, N.; Woo, C.; Bruns, C. J.; Ruchirawat, S.; Thasana, N. Synthesis and biological activities of azalamellarins. Chem. Asian. J. 2010, 5, 2113-2123.
3) Worayuthakarn, R.; Boonya-udtayan, S.; Arom-oon, E.; Ploypradith, P.; Ruchirawat, S.; Thasana, N. Synthesis of unsymmetrical benzil licoagrodione. J. Org. Chem. 2008, 73, 7432-7435.
4) Thasana, N.; Bjerke-Kroll, B.; Ruchirawat, S. A facile synthesis of telisatin A via microwave-promoted annulation and Reformatsky reaction. Synlett 2008, 505-508.
5) Thasana, N.; Worayuthakarn, R.; Kradanrat, P.; Hohn, E.; Young, L.; Ruchirawat, S. Copper(I)-mediated and microwave-assisted Caryl-Ocarboxylic coupling: Synthesis of benzopyaranones and isolamellarin alkaloids. J. Org. Chem. 2007, 72, 9379-9382.
6) Worayuthakarn, R.; Thasana, N.; Ruchirawat, S. Three distinct reactions of 3,4-dihydroisoquinolines with azlactones: Novel synthesis of imidazoloisoquinolin-3-ones, benzo[a]quinolizin-4-ones, and benzo[d]azocin-4-ones. Org. Lett. 2006, 8, 5845-5848..