Chun-Chen Liao

Anti-Influenza Drug Discovery: Structure-Activity Relationship and Mechanistic Insight into Novel Angelicin Derivatives

By using a cell-based high throughput screening campaign, a novel angelicin derivative 6a was identified to inhibit influenza A (H1N1) virus induced cytopathic effect in Madin-Darby canine kidney cell culture in low micromolar range. Detailed structure-activity relationship studies of 6a revealed that the angelicin scaffold is essential for activity in pharmacophore B, while meta-substituted phenyl/2-thiophene rings are optimal in pharmacophore A and C. The optimized lead 4-methyl-9-phenyl-8-(thiophene-2-carbonyl)-furo[2,3-h]chromen-2-one (8g, IC(50) = 70 nM) showed 64-fold enhanced activity compared to the high throughput screening (HTS) hit 6a. Also, 8g was found effective in case of influenza A (H3N2) and influenza B virus strains similar to approved anti-influenza drug zanamivir (4). Preliminary mechanistic studies suggest that these compounds act as anti-influenza agents by inhibiting ribonucleoprotein (RNP) complex associated activity and have the potential to be developed further, which could form the basis for developing additional defense against influenza pandemics.

Design and Synthesis of Tetrahydropyridothieno[2,3-d]pyrimidine Scaffold Based Epidermal Growth Factor Receptor (EGFR) Kinase Inhibitors: The Role of Side Chain Chirality and Michael Acceptor Group for Maximal Potency

HTS hit 7 was modified through hybrid design strategy to introduce a chiral side chain followed by introduction of Michael acceptor group to obtain potent EGFR kinase inhibitors 11 and 19. Both 11 and 19 showed over 3 orders of magnitude enhanced HCC827 antiproliferative activity compared to HTS hit 7 and also inhibited gefitinib-resistant double mutant (DM, T790M/L858R) EGFR kinase at nanomolar concentration. Moreover, treatment with 19 shrinked tumor in nude mice xenograft model.

Fast-Forwarding Hit to Lead: Aurora and Epidermal Growth Factor Receptor Kinase Inhibitor Lead Identification

A focused library of furanopyrimidine (350 compounds) was rapidly synthesized in parallel reactors and in situ screened for Aurora and epidermal growth factor receptor (EGFR) kinase activity, leading to the identification of some interesting hits. On the basis of structural biology observations, the hit 1a was modified to better fit the back pocket, producing the potent Aurora inhibitor 3 with submicromolar antiproliferative activity in HCT-116 colon cancer cell line. On the basis of docking studies with EGFR hit 1s, introduction of acrylamide Michael acceptor group led to 8, which inhibited both the wild and mutant EGFR kinase and also showed antiproliferative activity in HCC827 lung cancer cell line. Furthermore, the X-ray cocrystal study of 3 and 8 in complex with Aurora and EGFR, respectively, confirmed their hypothesized binding modes. Library construction, in situ screening, and structure-based drug design (SBDD) strategy described here could be applied for the lead identification of other kinases.

Synthesis of angularly and linearly fused triquinanes via the common intramolecular Diels-Alder adduct of a masked o-benzoquinone☆

Angularly and linearly fused triquinanes 10 and 15 were synthesized from catechol derivative 1 via a common masked o-benzoquinone 4 in 12 and 13 steps respectively. Intramolecular Diels-Alder reaction, photochemical oxa-di-π-methane rearrangement, and reductive ring opening of cyclopropyl ketone with SmI2 were the key steps.

Syntheses of optically pure conduramines via the strategy of hetero Diels-Alder reaction of masked o-benzoquinones with homochiral nitroso dienophiles.

Highly stereoselective hetero Diels-Alder reactions of masked o-benzoquinones (MOBs) with homochiral nitroso dienophiles are described along with their application in the syntheses of (+)-ent-conduramine F-1, (+)-conduramine E-1, (-)-conduramine A-1, (+)-conduramine A-1 tetraacetate, and (-)-ent-conduramine A-1 tetraacetate.

Domino retro Diels–Alder/Diels–Alder reaction: an efficient protocol for the synthesis of highly functionalized bicyclo[2.2.2]octenones and bicyclo[2.2.2]octadienones

A novel and convenient approach, the domino retro Diels-Alder/Diels-Alder reaction sequence for highly stereo- and regioselective synthesis of various bicyclo[2.2.2]octenone and bicyclo[2.2.2]octadienone derivatives is presented. Thus, the masked o-benzoquinones (MOBs) 2a-e generated by the pyrolysis of the respective dimers 3a-e participated in this novel synthetic strategy with a variety of olefinic and acetylenic dienophiles at 220 degrees C to provide the title compounds in good to excellent yields.

Carbohydrate‐Templated Asymmetric Diels–Alder Reactions of Masked ortho‐Benzoquinones for the Synthesis of Chiral Bicyclo[2.2.2]oct‐5‐en‐2‐ones

Bicyclo[2.2.2]oct-5-en-2-ones have been widely applied in natural product synthesis for several decades. Highly reactive 6,6-dialkoxycyclohexa-2,4-dienones (namely, masked o-benzoquinones or MOBs) and their orthoquinol variants, which can be conveniently generated by oxidation of the corresponding 2-alkoxyand 2-alkylphenols in an alcoholic solvent, are often used for synthesizing the bicyclo[2.2.2]oct-5-en-2-ones in racemic form through in situ intraor intermolecular Diels–Alder reactions with various dienophiles. However, two major hurdles are frequently encountered in these studies: avoiding the self-dimerization of the MOBs and preparing optically pure enantiomers. For example, oxidative addition of 2-methoxyphenol with methanol led to a MOB intermediate, which immediately selfdimerized to give the [4+2] cycloadducts. When an allyl or homoallyl alcohol was used in the reaction, a racemic mixture of the intramolecular cyclic products was obtained in very low yield. For the synthesis of the chiral forms, (S)-1-phenylethanol (1) was initially studied. However, the reaction of 2allyloxyphenol (2) with 1 in the presence of PhI(OCOCF3)2, via theMOB intermediates 3 and 4, furnished diastereomers 5 and 6 in only 15% and 9% yields, respectively (Scheme 1). We report herein a new and straightforward asymmetric methodology that involves carbohydrates as chiral auxiliaries and that tackles these problems. Our strategy, as illustrated in Scheme 2, entailed a threestep protocol. Coupling of the 2,3,4,6-tetra-O-protected hexopyranose 7 with a catechol 8 by Mitsunobu-type glycosylation could give the phenolic derivative 9. Oxidative assembly of 9 with an alkenyl alcohol 10 would yield the MOB intermediate 11, which could undergo intramolecular [4+2] cycloaddition to furnish the adduct 12 in a one-pot

Synthetic applications of masked o-benzoquinones. A novel total synthesis of (±)forsythide aglucone dimethyl ester☆

The title compound has been synthesized from methyl vanillate in 10 steps and in a 15% overall yield; the Diels-Alder reaction of a masked o-benzoquinone and the oxa-di-π methane rearrangement are the key reactions.

Inverse-electron-demand Diels–Alder reactions of masked o-benzoquinones with enol ethers and styrene

Abstract Regio- and stereoslective inverse-electron-demand Diels–Alder reactions of masked o -benzoquinones (MOBs) 1a – 1h derived from the corresponding 2-methoxyphenols 2a – 2h with benzyl vinyl ether, dihydrofuran and styrene to afford the highly functionalized bicyclo[2.2.2]octenone derivatives are described. The MOBs having electron-deficient substituents were found to undergo more facile Diels–Alder cycloadditions with these dienophiles. The electron-rich dienophile dihydropyran is not a suitable 2π-partner for MOBs. Attempts are made to explain the observed regiochemistry of these Diels–Alder cycloadditions in terms of frontier molecular orbital theory.

Stereoselective synthesis of (±)-(13E)-2-oxo-5α-cis-17α,20α-cleroda-3,13-dien-15-oic acid, and alleged cis-clerodane diterpenic acid

Abstract A stereocontrolled synthesis of the title acid (±)- 1 in 19 steps and 6 % overall yield is described. The structure of (±)- 1 was confirmed by X-ray diffraction study of its ethyl ester. The structure of our synthetic (±)- 1 differs from that of the alleged natural product.