Poonsakdi Ploypradith

Cytotoxicities and structure-activity relationships of natural and unnatural lamellarins toward cancer cell lines.

Shedding light on the lamellarins: Structural determinants for potent cytotoxic activity toward various cancer cell lines were systematically investigated to establish SARs for the marine alkaloids in the lamellarin family. The C5C6 double bond ensures not only the planarity of the D‐ring, but also proper alignment of the substituents on the E‐ring with their respective moieties of the target. The importance of the C7 OH group is also revealed for the first time.

Generation of ortho-Quinone Methides by p-TsOH on Silica and Their Hetero-Diels―Alder Reactions with Styrenes

2-Arylchromans were readily prepared from the hetero-Diels-Alder reactions of styrenes with the ortho-quinone methides (o-QMs) which, in turn, were generated by treating the MOM-protected benzylacetate derivatives with p-TsOH immobilized on silica (PTS-Si) in toluene under mild conditions (0 degrees C to rt). The corresponding chromans were obtained in moderate to excellent yields (42-97%) and in moderate to excellent diastereoselectivity (up to >99:1).

Further developments in the synthesis of lamellarin alkaloids via direct metal–halogen exchange

Direct metal–halogen exchange of 2-bromopyrrole carbonate derivatives with tert-butyllithium followed by the intramolecular lactonization of the resulting 2-pyrrole anion onto the carbonate provided the corresponding lamellarins in moderate to good yield. The lamellarin framework could be obtained from the direct metal–halogen exchange strategy in a 26–33% overall yield over 5–6 steps.

A convergent general strategy for the functionalized 2-aryl cycloalkyl-fused chromans: intramolecular hetero-Diels-Alder reactions of ortho-quinone methides.

adduct isolated from Brosimum rubescens, showed potent inhibition of the binding of 5a-dihydrotestosterone (DHT) with the androgen receptor. Parvifolol A (2 ; Scheme 1), a natural product isolated from Gnetum parvifolium, was evaluated for the inhibitory activity in the Maillard reaction (protein glycation) associated with diabetic complications and aging of the skin. Compound 3 was synthesized and studied as an estradiol analogue. Some tricyclic 2-aryl-3,4cycloalkyl-fused benzopyrans (4, 5 ; Scheme 1) were synthesized and investigated for their high affinity to and selectivity for the estrogen receptor b over the a. Some synthetic methods have been developed for chromans by hetero-Diels–Alder (HDA) reactions. However, despite the presence of the 2-aryl group in some natural products and synthetic compounds, the synthesis of 2-aryl3,4-cycloalkyl-fused chromans has been relatively unexplored, partly due to the susceptible nature of styrenes to polymerization. To date, the reported syntheses have been largely performed for the 2-alkylcycloalkyl-fused chromans and pyranobenzopyrans. In addition, modifications on the cycloalkyl-fused rings would be difficult because the cycloalkyl or pyranyl moieties are nonfunctionalized. Moreover, different strategies were required for cyclopentyland cyclohexyl-fused compounds (4, 5). Thus, developing a general synthetic strategy for the tricyclic core of 2-aryl-3,4-cycloalkyl-fused chromans with defined stereocenters (C2, C3, and C4) and functionalizable moieties on the cycloalkyl ring would be pivotal. Recently, as part of our research in the use of solid-supported reagents in organic synthesis, our group has reported the successful generation of o-QMs and their intermolecular HDA reactions with styrene derivatives under mild conditions mediated by p-toluenesulfonic acid (p-TsOH) immobilized on silica (PTS-Si) in toluene. We now envisioned that PTS-Si could be employed to generate ortho-quinone methide (o-QM), which, upon reacting intramolecularly with the tethered dienophile (i.e. , styrenes), could form the tricyclic 2-aryl-3,4-cycloalkyl-fused chroman. As shown retrosynthetically in Scheme 2, the precursors for the intramolecular HDA reactions would be derived from aldol condensation between the benzaldehyde derivative (6) and ketone (X= H; Y=Me) or the acetophenone derivative (7) and the aldehyde (X=Me; Y=H). Synthesis of these cycloalkyl-fused chroman systems would be highly convergent and requires a similar strategy to assemble the precursors for the intramolecular o-QM/HDA reactions. [a] Dr. J. Tummatorn, Prof. Dr. S. Ruchirawat, Dr. P. Ploypradith Laboratory of Medicinal Chemistry, Chulabhorn Research Institute Vipavadee-Rangsit Highway, Bangkok 10210 (Thailand) Fax: (+662) 574-2027 E-mail : poonsakdi@cri.or.th [b] Prof. Dr. S. Ruchirawat, Dr. P. Ploypradith Program in Chemical Biology, Chulabhorn Graduate Institute Vipavadee-Rangsit Highway, Bangkok 10210 (Thailand) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.200902403. Scheme 1. Examples of 2-arylcycloalkyl-fused chromans (shown with relative stereochemistry).

Assessing the drug-likeness of lamellarins, a marine-derived natural product class with diverse oncological activities.

Natural products currently represent an underutilized source of leads for the pharmaceutical industry, especially when one considers that almost 50% of all drugs were either derived from such sources or are very closely related. Lamellarins are a class of natural products with diverse biological activities and have entered into preclinical development for the treatment of multidrug-resistant tumors. Although these compounds demonstrated good cell penetration, as observed by their low microM activity in whole cell models, they have not been extensively profiled from a physicochemical point of view, and this is the goal of this study. For this study, we have determined the experimental logP values of a set of 25 lamellarins, given it is the single most important parameter in determining multiple ADMET parameters. We also discuss the relationship between this natural product class, natural product derivatives in development and on the market, oral marketed drugs, as well as drug molecules in development, using a range of physicochemical parameters in conjunction with principal components analysis (PCA). The impact of this systematic analysis on our ongoing medicinal chemistry strategy is also discussed.

Designing New Analogs for Streamlining the Structure of Cytotoxic Lamellarin Natural Products

Despite the therapeutic potential of marine-derived lamellarin natural products, their preclinical development has been hampered by their lipophilic nature, causing very poor aqueous solubility. In order to develop more drug-like analogs, their structure was streamlined in this study from both the cytotoxic activity and lipophilicity standpoints. First, a modified total synthetic route was successfully devised to construct a library of 59 systematically designed lamellarin analogs, which were then subjected to cytotoxicity and log P determinations. Along with the 25 first-generation lamellarins previously synthesized in our laboratory, the structure-activity and structure-lipophilicity relationships were extensively evaluated. Our results clearly indicated the additional structural requirements around the lamellarin skeleton which, when combined with those reported previously, can provide invaluable guidance for further modifications to increase the aqueous solubility of these compounds.

Divergent Strategy for the Diastereoselective Synthesis of the Tricyclic 6,7-Diaryltetrahydro-6H-benzo[c]chromene Core via Pt(IV)-Catalyzed Cycloaddition of o-Quinone Methides and Olefin Ring-Closing Metathesis

A divergent strategy for the synthesis of the tricyclic 6,7-diaryltetrahydro-6H-benzo[c]chromene core was successfully developed. The 2,3-trans, 2,4-cis trisubstituted chroman moiety was formed via highly efficient and stereoselective Pt(IV)-catalyzed cycloaddition reactions of the corresponding quinone methides with chalcones. Subsequent steps provided the common diene alcohol, which underwent BF3·Et2O-mediated Et3SiH reduction and olefin ring-closing metathesis (RCM) using Ru(II) catalysts. The sequence of the final two steps provided a handle to diversify the stereochemical outcomes at C6 as well as C10a.

Facile and Divergent Synthesis of Lamellarins and Lactam-Containing Derivatives with Improved Drug Likeness and Biological Activities

With the goal to improve the aqueous solubility of lamellarins, the lactone ring in their skeleton was replaced with a lactam moiety in azalamellarins. However, the reported synthetic route produced such derivatives in very low yields. Hence, this study focused on developing an efficient simplified total synthetic scheme that could furnish both azalamellarins and the parent lamellarins from the same pyrrole ester intermediates. Subsequent comparative profiling revealed that the introduced lactone-to-lactam replacement rendered these molecules less lipophilic, whereas their cancer cytotoxicity remained equipotent to that of the parent compounds. Interestingly, their inhibitory activity was significantly enhanced towards the multifaceted GSK-3β enzyme. Our results clearly demonstrate the therapeutic potential of this promising class of marine-derived natural products and justify their further development, especially into anticancer agents.

Synthesis of unsymmetrical benzil licoagrodione.

A synthesis of unsymmetrical 1,2-diarylethane-1,2-dione is reported involving the intramolecular cyclization of anionic benzylic ester of the aryl benzyl ether followed by oxidation employing dioxirane. With the use of microwave irradiation, licoagrodione was prepared from Claisen rearrangement of the corresponding allyl phenyl ether 1,2-diketone readily available from the Lindlars reduction of the corresponding alkyne derivative. Subsequent removal of protecting groups then furnished the desired product.

Synthesis of Substituted 2-Arylindanes from E-(2-Stilbenyl)methanols via Lewis Acid-Mediated Cyclization and Nucleophililc Transfer from Trialkylsilyl Reagents

A preparative method for the synthesis of functionalized 2-arylindanes has been developed via the Lewis acid-mediated ring closure of stilbenyl methanols followed by nucleophilic transfer from trialkylsilyl reagents. The reactions gave the corresponding products in moderate to high yields and diastereoselectivity. The solvent as well as the nucleophile played an important role in determining the type(s) of product arising either from nucleophilic addition (indanes) or loss of a proton β to the indanyl-type carbocations (indenes). Electron-donating groups on the fused aromatic ring (Y and Z = OMe) or the presence of electron-withdrawing groups (NO2) on the nonfused Ar ring facilitate the cyclization. In contrast, the presence of electron-donating groups (OMe) on the nonfused Ar ring impedes the process. In the case of Cl on the nonfused Ar ring, temperature modulates the resonance versus inductive field effects on the overall reaction pathways involving cyclization to form the indanyl-type cation. Quantum chemical calculations supported the intermediacy of the carbocation species and the transfer of hydride from triethylsilane (Nu = H) to the indanyl-type cations to form the trans-1,2-disubstituted indane as the single diastereomer product.