Christina Chai

Name:

Organization: National University of Singapore

Department: Institute of Chemical & Engineering Sciences, Agency for Science Technology and Research (A*STAR), 1 Pesek Road, Jurong Island, Singapore 627833

Title:

Chemicals
References

Trisubstituted Thieno[3,2-b]pyrrole 5-Carboxamides as Potent Inhibitors of Alphaviruses

Co-reporter:Kuan-Chieh Ching; Yiu-Wing Kam; Andres Merits; Lisa F. P. Ng;Christina L. L. Chai

Journal of Medicinal Chemistry 2015 Volume 58(Issue 23) pp:9196-9213

Publication Date(Web):November 5, 2015

DOI:10.1021/acs.jmedchem.5b01047

Chikungunya virus (CHIKV) is a re-emerging vector-borne alphavirus and is transmitted to humans by Aedes mosquitoes. Despite the re-emergence of CHIKV as an epidemic threat, there is no approved effective antiviral treatment currently available for CHIKV. Herein, we report the synthesis and structure–activity relationship studies of a class of thieno[3,2-b]pyrroles and the discovery of a trisubstituted thieno[3,2-b]pyrrole 5-carboxamide 15c that exhibits potent inhibitory activity against in vitro CHIKV infection. Compound 15c displayed low micromolar activity (EC50 value of ca. 2 μM) and limited cytotoxic liability (CC50 > 100 μM) therefore furnishing a selectivity index of greater than 32. Notably, 15c not only controlled viral RNA production, but efficiently inhibited the expression of CHIKV nsP1, nsP3, capsid, and E2 proteins at a concentration as low as 2.5 μM. More importantly, 15c also demonstrated broad spectrum antiviral activity against other clinically important alphaviruses such as O’nyong–nyong virus and Sindbis virus.

Novel Arylalkenylpropargylamines as Neuroprotective, Potent, and Selective Monoamine Oxidase B Inhibitors for the Treatment of Parkinson’s Disease

Co-reporter:Paul B. Huleatt; Mui Ling Khoo; Yi Yuan Chua; Tiong Wei Tan; Rou Shen Liew; Balázs Balogh; Ruth Deme; Flóra Gölöncsér; Kalman Magyar; David P. Sheela; Han Kiat Ho; Beáta Sperlágh; Péter Mátyus;Christina L. L. Chai

Journal of Medicinal Chemistry 2015 Volume 58(Issue 3) pp:1400-1419

Publication Date(Web):January 28, 2015

DOI:10.1021/jm501722s

To develop novel neuroprotective agents, a library of novel arylalkenylpropargylamines was synthesized and tested for inhibitory activities against monoamine oxidases. From this, a number of highly potent and selective monoamine oxidase B inhibitors were identified. Selected compounds were also tested for neuroprotection in in vitro studies with PC-12 cells treated with 6-OHDA and rotenone, respectively. It was observed that some of the compounds tested yielded a marked increase in survival in PC-12 cells treated with the neurotoxins. This indicates that these propargylamines are able to confer protection against the effects of the toxins and may also be considered as novel disease-modifying anti-Parkinsonian agents, which are much needed for the therapy of Parkinson’s disease.

3-DeazaneplanocinA and NeplanocinA Analogues and Their Effects on Apoptotic Cell Death

Co-reporter:Dr. Eric K. W. Tam;Dr. Tuan Minh Nguyen;Cheryl Z. H. Lim;Puay Leng Lee;Zhimei Li;Xia Jiang;Dr. Sridhar Santhanakrishnan;Tiong Wei Tan;Yi Ling Goh;Sze Yue Wong;Haiyan Yang;Esther H. Q. Ong;Dr. Jeffrey Hill;Dr. Qiang Yu; Christina L. L. Chai

ChemMedChem 2015 Volume 10( Issue 1) pp:173-182

Publication Date(Web):

DOI:10.1002/cmdc.201402315

Abstract

3-Deazaneplanocin A (DzNep) is a potential epigenetic drug for the treatment of various cancers. DzNep has been reported to deplete histone methylations, including oncogenic EZH2 complex, giving rise to epigenetic modifications that reactivate many silenced tumor suppressors in cancer cells. Despite its promise as an anticancer drug, little is known about the structure–activity relationships of DzNep in the context of epigenetic modifications and apoptosis induction. In this study, a number of analogues of DzNep were examined for DzNep-like ability to induce synergistic apoptosis in cancer cells in combination with trichostatin A, a known histone deacetylase (HDAC) inhibitor. The structure–activity relationship data thus obtained provide valuable information on the structural requirements for biological activity. The studies identified three compounds that show similar activities to DzNep. Two of these compounds show good pharmacokinetics and safety profiles. Attempts to correlate the observed synergistic apoptotic activities with measured S-adenosylhomocysteine hydrolase (SAHH) inhibitory activities suggest that the apoptotic activity of DzNep might not be directly due to its inhibition of SAHH.

Synthesis of Mimics of Pramanicin from Pyroglutamic Acid and Their Antibacterial Activity

Co-reporter:Song Wei Benjamin Tan, Christina L. L. Chai, Mark G. Moloney, and Amber L. Thompson

The Journal of Organic Chemistry 2015 Volume 80(Issue 5) pp:2661-2675

Publication Date(Web):February 3, 2015

DOI:10.1021/jo502810b

Epoxypyrrolidinones are available by epoxidation of carboxamide-activated bicyclic lactam substrates derived from pyroglutamate using aqueous hydrogen peroxide and tertiary amine catalysis. In the case of an activating Weinreb carboxamide, further chemoselective elaboration leads to the efficient formation of libraries of epoxyketones. Deprotection may be achieved under acidic conditions to give epoxypyroglutaminols, although the ease of this process can be ameliorated by the presence of internal hydrogen bonding. Bioassay against S. aureus and E. coli indicated that some compounds exhibit antibacterial activity. These libraries may be considered to be structural mimics of the natural products pramanicin and epolactaene. More generally, this outcome suggests that interrogation of bioactive natural products is likely to permit the identification of “privileged” structural scaffolds, providing frameworks suitable for optimization in a short series of chemical steps that may accelerate the discovery of new antibiotic chemotypes. Further optimization of such systems may permit the rapid identification of novel systems suitable for antibacterial drug development.

Synthesis of 3-acyltetramates by side chain manipulation and their antibacterial activity

Co-reporter:Song Wei Benjamin Tan, Christina L. L. Chai and Mark G. Moloney

Organic & Biomolecular Chemistry 2014 vol. 12(Issue 11) pp:1711-1716

Publication Date(Web):04 Feb 2014

DOI:10.1039/C4OB00095A

An efficient approach for the introduction of 3-acyl side chain groups onto a core tetramate system, which are suitable for further manipulation by nucleophilic displacement or Horner–Wadsworth–Emmons coupling, provides access to a diverse library of substituted tetramates related to two distinct classes of natural products, equisetin and pramanicin. Assessment against S. aureus and E. coli indicated that some compounds exhibit significant antibacterial activity, providing unusual leads for further optimisation in the drug discovery process.

Synthesis of Neplanocin A and Its 3′-Epimer via an Intramolecular Baylis–Hillman Reaction

Co-reporter:Yun Xuan Tan, Sridhar Santhanakrishnan, Hai Yan Yang, Christina L. L. Chai, and Eric Kwok Wai Tam

The Journal of Organic Chemistry 2014 Volume 79(Issue 17) pp:8059-8066

Publication Date(Web):August 14, 2014

DOI:10.1021/jo501248e

The key cyclopentenyl intermediate 11b was synthesized in 4 steps from d-ribose in 41% overall yield via an efficient intramolecular Baylis–Hillman reaction. This novel key intermediate can be modified easily and transformed to neplanocin A (1a) and its 3′-epimer (1b).

Tri-substituted imidazole analogues of SB203580 as inducers for cardiomyogenesis of human embryonic stem cells

Co-reporter:Joo-Leng Low, Gerrit Jürjens, Jayasree Seayad, Jasmine Seow, Sherwin Ting, Filip Laco, Shaul Reuveny, Steve Oh, Christina L.L. Chai

Bioorganic & Medicinal Chemistry Letters 2013 Volume 23(Issue 11) pp:3300-3303

Publication Date(Web):1 June 2013

DOI:10.1016/j.bmcl.2013.03.103

The p38α mitogen-activated protein kinase (MAPK) inhibitor SB203580 had been reported to enhance the cardiomyogenesis of human embryonic stem cells (hESCs). To investigate if tri-substituted imidazole analogues of SB203580 are equally effective inducers for cardiomyogenesis of hESCs, and if there is a correlation between p38α MAPK inhibition and cardiomyogenesis, we designed and synthesized a series of novel tri-substituted imidazoles with a range of p38α MAPK inhibitory activities. Our studies demonstrated that suitably designed analogues of SB203580 can also be inducers of cardiomyogenesis in hESCs and that cell growth is affected by changes in the imidazole structures.

N-Heterocyclic Carbene (NHC) Catalyzed Cycloaddition of CO2 to N-Tosyl Aziridines: Regio and Stereoselective Synthesis of Oxazolidin-2-ones

Co-reporter:Dr. Jayasree Seayad;Dr. Abdul Majeed Seayad;Dr. Joseph Kok Peng Ng;Dr. Christina Li Lin Chai

ChemCatChem 2012 Volume 4( Issue 6) pp:774-777

Publication Date(Web):

DOI:10.1002/cctc.201200080

Control of chemoselectivity in Dieckmann ring closures leading to tetramic acids

Co-reporter:Yong-Chul Jeong, Muhammad Anwar, Tuan Minh Nguyen, Benjamin Song Wei Tan, Christina Li Lin Chai and Mark G. Moloney

Organic & Biomolecular Chemistry 2011 vol. 9(Issue 19) pp:6663-6669

Publication Date(Web):20 Jun 2011

DOI:10.1039/C1OB05816A

An efficient strategy for the control of the chemoselectivity in Dieckmann ring closures leading to tetramic acids derived from serine and α-methyl serine is reported, and this provides pathways to diversely substituted systems from a common starting material.

Exploring Aigialomycin D and Its Analogues as Protein Kinase Inhibitors for Cancer Targets

Co-reporter:Jin Xu, Anqi Chen, Mei-Lin Go, Kassoum Nacro, Boping Liu, and Christina L. L. Chai

ACS Medicinal Chemistry Letters 2011 Volume 2(Issue 9) pp:662

Publication Date(Web):July 17, 2011

DOI:10.1021/ml200067t

The natural product aigialomycin D (1) is a member of the resorcylic acid lactone (RAL) family possessing protein kinase inhibitory activities. This paper describes the synthesis of aigialomycin D and a series of its analogues and their activity for the inhibition of protein kinases related to cancer pathways. A preliminary study of these compounds in the inhibition of CDK2/cyclin A kinase has found that aigialomycin D and analogues 11 and 23 are moderate CDK2/cyclin A inhibitors with IC50 values of ca. 20 μM. Kinase profiling of aigialomycin D against a panel of kinases has led to the identification of MNK2 as a promising target (IC50 = 0.45 μM), and preliminary structure–activity relationship studies have been carried out to identify the essential functional groups for activity.Keywords: Aigialomycin D; CDK2; kinase inhibitor; MNK; resorcylic acid lactone

Synthesis and potent cytotoxic activity of 8- and 9-anilinophenanthridine-7,10-diones

Co-reporter:Paul H. Bernardo, Jasmeet K. Khanijou, Tze Hau Lam, Joo Chuan Tong, Christina L.L. Chai

Tetrahedron Letters 2011 Volume 52(Issue 1) pp:92-94

Publication Date(Web):5 January 2011

DOI:10.1016/j.tetlet.2010.10.170

A series of 8-anilino and 9-anilinophenanthridine-7,10-diones was prepared and screened against various cancer cell lines to measure anti-proliferative activity. The compounds tested display potent cytotoxic activity in the micromolar and sub-micromolar range. These compounds are promising new leads for developing anticancer compounds.The synthesis of 8- and 9-anilinophenanthridine-7,10-diones is described. The potent cytotoxic activity against several cancer cell lines is also presented.

Concise, efficient and practical assembly of bromo-5,6-dimethoxyindole building blocks

Co-reporter:Paul B. Huleatt, Jacelyn Lau, Sheena Chua, Yun Lei Tan, Hung Anh Duong, Christina L.L. Chai

Tetrahedron Letters 2011 Volume 52(Issue 12) pp:1339-1342

Publication Date(Web):23 March 2011

DOI:10.1016/j.tetlet.2011.01.076

A concise, efficient and simple route to a series of bromoindole building blocks is described. The synthetic routes are highlighted by purification-free preparation of o-nitrocinnamate intermediates and clean, modified Cadogan indole syntheses. The scope of this indole synthesis has been explored and expanded through the use of a range of solvents and easily removable phosphine reagents.

A pattern recognition approach to 14-epi-hydrophenanthrene core of the morphine alkaloids based on shikimic acid

Co-reporter:Tung N. Dinh, Anqi Chen, Christina L.L. Chai

Tetrahedron 2011 67(19) pp: 3363-3368

Publication Date(Web):

DOI:10.1016/j.tet.2011.03.063

Copper-Catalyzed Diacetoxylation of Olefins using PhI(OAc)2 as Oxidant

Co-reporter:Jayasree Seayad, Abdul Majeed Seayad and Christina L. L. Chai

Organic Letters 2010 Volume 12(Issue 7) pp:1412-1415

Publication Date(Web):March 11, 2010

DOI:10.1021/ol902813m

Copper(I) or -(II) salts with weakly coordinating anions catalyze the diacetoxylation of olefins efficiently in the presence of PhI(OAc)2 as the oxidant under mild conditions. The reaction is effective for aryl, aryl alkyl, as well as aliphatic terminal and internal olefins forming the corresponding vicinal diacetoxy compounds in 70−85% yields and dr (syn/anti) of up to 5.2. Under these conditions, homoallylic alcohols formed the corresponding tetrahydrofuran derivatives in high yields.

Highly Enantioselective Titanium-Catalyzed Cyanation of Imines at Room Temperature

Co-reporter:Abdul Majeed Seayad, Balamurugan Ramalingam, Kazuhiko Yoshinaga, Takushi Nagata and Christina L. L. Chai

Organic Letters 2010 Volume 12(Issue 2) pp:264-267

Publication Date(Web):December 21, 2009

DOI:10.1021/ol902540h

A highly active and enantioselective titanium-catalyzed cyanation of imines at room temperature is described. The catalyst used is a partially hydrolyzed titanium alkoxide (PHTA) precatalyst together with a readily available N-salicyl-β-aminoalcohol ligand. Up to 98% ee was obtained with quantitative yields in 15 min of reaction time using 5 mol % of the catalyst. Various N-protecting groups such as benzyl, benzhydryl, Boc, and PMP are tolerated.

Efficient Formal Synthesis of Oseltamivir Phosphate (Tamiflu) with Inexpensive d-Ribose as the Starting Material

Co-reporter:Hiroshi Osato, Ian L. Jones, Anqi Chen and Christina L. L. Chai

Organic Letters 2010 Volume 12(Issue 1) pp:60-63

Publication Date(Web):November 25, 2009

DOI:10.1021/ol9024716

An efficient formal synthesis of oseltamivir phosphate (Tamiflu) has been achieved in 12 steps with use of the inexpensive and highly abundant d-ribose as the starting material. This concise alternative route does not utilize protecting groups and features the introduction of 3-pentylidene ketal as the latent 3-pentyl ether, the use of a highly efficient RCM reaction to form the Tamiflu skeleton, and selective functional group manipulations.

Structural Insights into the Design of Small Molecule Inhibitors That Selectively Antagonize Mcl-1

Co-reporter:Paul H. Bernardo ; Thirunavukkarasu Sivaraman ; Kah-Fei Wan ; Jin Xu ; Janarthanan Krishnamoorthy ; Chun Meng Song ; Liming Tian ; Jasmine S. F. Chin ; Diane S. W. Lim ; Henry Y. K. Mok ; Victor C. Yu ; Joo Chuan Tong ;Christina L. L. Chai

Journal of Medicinal Chemistry 2010 Volume 53(Issue 5) pp:2314-2318

Publication Date(Web):February 16, 2010

DOI:10.1021/jm901469p

The screening of a small focused library of rhodanine derivatives as inhibitors of Bcl-2 proteins led to the discovery of two structurally related compounds with different binding profiles against the Bcl-XL and the Mcl-1 proteins. Subsequent NMR studies with mutant proteins and in silico docking studies provide a possible rationale for the observed specificity.

A Remarkable Titanium-Catalyzed Asymmetric Strecker Reaction using Hydrogen Cyanide at Room Temperature

Co-reporter:Balamurugan Ramalingam;Abdul Majeed Seayad;Li Chuanzhao;Marc Garl;Kazuhiko Yoshinaga;Manabu Wadamoto;Takushi Nagata;Christina L. L. Chai

Advanced Synthesis & Catalysis 2010 Volume 352( Issue 13) pp:2153-2158

Publication Date(Web):

DOI:10.1002/adsc.201000462

Abstract

Close to perfect enantioselectivity (up to 98% ee) is obtained for the formation of amino nitriles using hydrogen cyanide (HCN) as the cyanide source at room temperature for the first time. In an operationally simple process, the catalyst generated from a partially hydrolyzed titanium alkoxide (PHTA) and (S)-N-salicyl-β-amino alcohol ligand, catalyzes the cyanation of imines in a short reaction time.

A fast and straightforward route towards the synthesis of the lissoclimide class of anti-tumour agents

Co-reporter:Tuan Minh Nguyen, Nguyen Quang Vu, Jean-Jacques Youte, Jacelyn Lau, Angie Cheong, Ying San Ho, Benjamin S.W. Tan, Kanagasundaram Yoganathan, Mark S. Butler, Christina L.L. Chai

Tetrahedron 2010 66(47) pp: 9270-9276

Publication Date(Web):

DOI:10.1016/j.tet.2010.09.031

l-Threonine-catalysed asymmetric α-hydroxymethylation of cyclohexanone: application to the synthesis of pharmaceutical compounds and natural products

Co-reporter:Anqi Chen, Jin Xu, Winnie Chiang, Christina L.L. Chai

Tetrahedron 2010 66(7) pp: 1489-1495

Publication Date(Web):

DOI:10.1016/j.tet.2009.11.100

Organic polymer composites as robust, non-covalent supports of metal salts

Co-reporter:Yeap Hung Ng, Mian Wang, Hong Han and Christina L. L. Chai

Chemical Communications 2009 (Issue 37) pp:5530-5532

Publication Date(Web):25 Aug 2009

DOI:10.1039/B905283F

A novel organic polymer composite for the encapsulation of metal catalysts and applications to synthesis are described here.

Total Synthesis of (±)-Cordypyridones A and B and Related Epimers

Co-reporter:Ian L. Jones, Felicity K. Moore and Christina L. L. Chai

Organic Letters 2009 Volume 11(Issue 23) pp:5526-5529

Publication Date(Web):October 29, 2009

DOI:10.1021/ol9023437

Efficient racemic synthesis of two antibacterial and antimalarial natural products, cordypyridones A and B, was achieved from inexpensive, commercially available starting materials in an overall yield of 15% (8% and 7%, respectively). This convergent synthesis utilizes a key coupling step of two fragments and the subsequent functional group transformations lead to the target compounds and their 8-epi-analogues.

Highly efficient catalytic routes to spiroketal motifs

Co-reporter:Selvasothi Selvaratnam, Joanne H.H. Ho, Paul B. Huleatt, Barbara A. Messerle, Christina L.L. Chai

Tetrahedron Letters 2009 50(10) pp: 1125-1127

Publication Date(Web):

DOI:10.1016/j.tetlet.2008.12.075

Iron-Catalysed sp3–sp3 Cross-Coupling Reactions of Unactivated Alkyl Halides with Alkyl Grignard Reagents

Co-reporter:Krishna G. Dongol;Huishi Koh;Manisankar Sau;Christina L. L. Chai

Advanced Synthesis & Catalysis 2007 Volume 349(Issue 7) pp:

Publication Date(Web):18 MAY 2007

DOI:10.1002/adsc.200600383

Iron-catalysed sp³–sp³ Kumada coupling with primary and secondary alkyl halides (RX) and alkyl Grignard reagents has been achieved in low to good yields depending on the nature of the R group.

Structure–activity delineation of quinones related to the biologically active Calothrixin B

Co-reporter:Paul H. Bernardo, Christina L.L. Chai, Maurice Le Guen, Geoffrey D. Smith, Paul Waring

Bioorganic & Medicinal Chemistry Letters 2007 Volume 17(Issue 1) pp:82-85

Publication Date(Web):1 January 2007

DOI:10.1016/j.bmcl.2006.09.090

Quinones such as Calothrixins A and B display a range of biological properties. As part of our ongoing studies to elucidate the mechanism of action of the Calothrixins, several related quinones were synthesized and tested for biological activity. The results of the structure–activity relationship (SAR) studies are reported here.The biological activities of Calothrixin B and six related analogues against three cell lines are reported. The results of the structure–activity relationship study are discussed.

Corrigendum to Cardiomyocyte differentiation of pluripotent stem cells with SB203580 analogues correlates with Wnt pathway CK1 inhibition independent of p38 MAPK signaling [J Mol Cell Cardiol 80 (2015) 56–70]

Co-reporter:Filip Laco, Joo-Leng Low, Jasmin Seow, Tsung Liang Woo, Qixing Zhong, Jayasree Seayad, Zhenfeng Liu, Heming Wei, Shaul Reuveny, David A. Elliott, Christina L.L. Chai, Steve K.W. Oh

Journal of Molecular and Cellular Cardiology (August 2015) Volume 85() pp:294

Publication Date(Web):1 August 2015

DOI:10.1016/j.yjmcc.2015.05.014

Structure−Activity Relationship Studies of Phenanthridine-Based Bcl-XL Inhibitors

Co-reporter:Paul H. Bernardo ; Kah-Fei Wan ; Thirunavukkarasu Sivaraman ; Jin Xu ; Felicity K. Moore ; Alvin W. Hung ; Henry Y. K. Mok ; Victor C. Yu ;Christina L. L. Chai

Journal of Medicinal Chemistry () pp:

Publication Date(Web):

DOI:10.1021/jm8005433

Despite their structural similarities, the natural products chelerythrine (5) and sanguinarine (6) target different binding sites on the pro-survival Bcl-XL protein. This paper details the synthesis of phenanthridine-based analogues of the natural products that were used to probe this difference in binding profiles. The inhibitory constants for these compounds were then measured in a fluorescence polarization assay against Bcl-XL and the tagged Bak-BH3 peptide. The results led to structure−activity relationship studies, which identified the structural motifs required for binding-site specificity as well as inhibitory activity. We also identified synthetic analogues of the natural products that display similar binding modes but with more potent IC50 values.

Organic polymer composites as robust, non-covalent supports of metal salts

Co-reporter:Yeap Hung Ng, Mian Wang, Hong Han and Christina L. L. Chai

Chemical Communications 2009(Issue 37) pp:

Publication Date(Web):

DOI:10.1039/B905283F

Control of chemoselectivity in Dieckmann ring closures leading to tetramic acids

Co-reporter:Yong-Chul Jeong, Muhammad Anwar, Tuan Minh Nguyen, Benjamin Song Wei Tan, Christina Li Lin Chai and Mark G. Moloney

Organic & Biomolecular Chemistry 2011 - vol. 9(Issue 19) pp:NaN6669-6669

Publication Date(Web):2011/06/20

DOI:10.1039/C1OB05816A

Synthesis of 3-acyltetramates by side chain manipulation and their antibacterial activity

Co-reporter:Song Wei Benjamin Tan, Christina L. L. Chai and Mark G. Moloney