Xu Bai

Name:

Organization: Jilin University

Department: The Center for Combinatorial Chemistry and Drug Discovery, The School of Pharmaceutical Sciences and The College of Chemistry

Title:

Chemicals
References

Reaction of Aldehydes/Ketones with Electron-Deficient 1,3,5-Triazines Leading to Functionalized Pyrimidines as Diels–Alder/Retro-Diels–Alder Reaction Products: Reaction Development and Mechanistic Studies

Co-reporter:Kai Yang, Qun Dang, Pei-Jun Cai, Yang Gao, Zhi-Xiang Yu, and Xu Bai

The Journal of Organic Chemistry 2017 Volume 82(Issue 5) pp:

Publication Date(Web):January 23, 2017

DOI:10.1021/acs.joc.6b02570

Catalytic inverse electron demand Diels–Alder (IEDDA) reactions of heterocyclic aza-dienes are rarely reported since highly reactive and electron-rich dienophiles are often found not compatible with strong acids such as Lewis acids. Herein, we disclose that TFA-catalyzed reactions of electron-deficient 1,3,5-triazines and electron-deficient aldehydes/ketones can take place. These reactions led to highly functionalized pyrimidines as products in fair to good yields. The reaction mechanism was carefully studied by the combination of experimental and computational studies. The reactions involve a cascade of stepwise inverse electron demand hetero-Diels–Alder (ihDA) reactions, followed by retro-Diels–Alder (rDA) reactions and elimination of water. An acid was required for both ihDA and rDA reactions. This mechanism was further verified by comparing the relative reactivity of aldehydes/ketones and their corresponding vinyl ethers in the current reaction system.

Organocatalytic Inverse-Electron-Demand Diels–Alder Reactions of Ketones with 1,3,5-Triazines

Co-reporter:Kai Yang;Qun Dang

European Journal of Organic Chemistry 2017 Volume 2017(Issue 14) pp:1922-1925

Publication Date(Web):2017/04/10

DOI:10.1002/ejoc.201700212

An organocatalytic version of the inverse-electron-demand Diels–Alder (IEDDA) reaction of 1,3,5-triazines was successfully developed. Hydrazine was used an effective organocatalyst for the direct IEDDA reaction of ketones with 1,3,5-triazines. This reaction has an expanded substrate scope relative to other 1,3,5-triazine IEDDA reactions and is also more operationally simple; thus, it is a succinct, economical, and green approach for the preparation of highly functionalized pyrimidines from readily available ketones.

Synthesis and Evaluation of 2-Alkylthio-4-(N-substituted sulfonamide)pyrimidine Hydroxamic Acids as Anti-myeloma Agents

Co-reporter:Jinbao Xiang;Crystal Leung;Zhuoqi Zhang;Cassie Hu;Chao Geng;Lili Liu;Lang Yi;Zhiwei Li;James Berenson

Chemical Biology & Drug Design 2016 Volume 87( Issue 3) pp:472-477

Publication Date(Web):

DOI:10.1111/cbdd.12678

A series of pyrimidine hydroxamic acids with a sulfide substituent at the second position and a sulfonamide substituent at the fourth position have been synthesized and evaluated for their activity against human myeloma cell line RPMI 8226. Several compounds exhibited significant anti-cancer potency. It was found that representative compound 6a selectively killed cancerous but not normal cells. Moreover, compound 6a was effective in causing apoptosis in RPMI 8226 cells and exhibited promising HDAC-inhibitory activities.

Discovery of Novel Tricyclic Thiazepine Derivatives as Anti-Drug-Resistant Cancer Agents by Combining Diversity-Oriented Synthesis and Converging Screening Approach

Co-reporter:Jinbao Xiang, Zhuoqi Zhang, Yan Mu, Xianxiu Xu, Sigen Guo, Yongjin Liu, Daniel P. Russo, Hao Zhu, Bing Yan, and Xu Bai

ACS Combinatorial Science 2016 Volume 18(Issue 5) pp:230

Publication Date(Web):April 15, 2016

DOI:10.1021/acscombsci.6b00010

An efficient discovery strategy by combining diversity-oriented synthesis and converging cellular screening is described. By a three-round screening process, we identified novel tricyclic pyrido[2,3-b][1,4]benzothiazepines showing potent inhibitory activity against paclitaxel-resistant cell line H460TaxR (EC50 < 1.0 μM), which exhibits much less toxicity toward normal cells (EC50 > 100 μM against normal human fibroblasts). The most active hits also exhibited drug-like properties suitable for further preclinical research. This redeployment of antidepressing compounds for anticancer applications provides promising future prospects for treating drug-resistant tumors with fewer side effects.Keywords: antidepressing; H460TaxR; redeployment; selective cytotoxicity; tricyclic thiazepine

Design, synthesis, and protein methyltransferase activity of a unique set of constrained amine containing compounds

Co-reporter:Hao Zhou, Xin Che, Guochen Bao, Na Wang, Li Peng, Kimberly D. Barnash, Stephen V. Frye, Lindsey I. James, Xu Bai

Bioorganic & Medicinal Chemistry Letters 2016 Volume 26(Issue 18) pp:4436-4440

Publication Date(Web):15 September 2016

DOI:10.1016/j.bmcl.2016.08.004

Epigenetic alterations relate to various human diseases, and developing inhibitors of Kme regulatory proteins is considered to be a new frontier for drug discovery. We were inspired by the known multicyclic ligands, UNC669 and UNC926, which are the first reported small molecule ligands for a methyl-lysine binding domain. We hypothesized that reducing the conformational flexibility of the key amine moiety of UNC669 would result in a unique set of ligands. Twenty-five novel compounds containing a fused bi- or tricyclic amine or a spirocyclic amine were designed and synthesized. To gauge the potential of these amine-containing compounds to interact with Kme regulatory proteins, the compounds were screened against a panel of 24 protein methyltransferases. Compound 13 was discovered as a novel scaffold that interacts with SETD8 and could serve as a starting point for the future development of PKMT inhibitors.

Electronic Effects on the cis/trans Selectivity in Formation of Isoxazolidine-Fused Eight-Membered Ring via an Intramolecular Nitrone-Alkene Cycloaddition

Co-reporter:Jinbao Xiang;Tong Zhu;Qun Dang

Chemistry of Heterocyclic Compounds 2016 Volume 52( Issue 8) pp:601-608

Publication Date(Web):2016 August

DOI:10.1007/s10593-016-1938-z

An intramolecular nitrone-alkene cycloaddition involving in situ generated nitrones demonstrated reaction profiles different from those previously reported for pyrimidine system. Tuning the electron density of the benzene ring had a significant effect on cis/trans selectivity. These reactions were useful for the synthesis of novel tricyclic hexahydrobenzo[b]isoxazolo[3,4-f][1, 4]diazocin-4(1H)-ones and hexahydroisoxazolo[3,4-f]pyrido[3,2-b][1, 4]diazocin-4(1H)-one under mild reaction conditions in good yields

Stereoselective Synthesis of 3-Carboxy-4,5-dihydropyrroles via an Intramolecular Iminium Ion Cyclization Reaction

Co-reporter:Jinbao Xiang, Hongxiang Xie, Zhuo Li, Qun Dang, and Xu Bai

Organic Letters 2015 Volume 17(Issue 15) pp:3818-3821

Publication Date(Web):July 27, 2015

DOI:10.1021/acs.orglett.5b01787

An efficient and practical method has been developed for the synthesis of trans-4,5-disubstituted 3-carboxy-4,5-dihydropyrroles via an intramolecular iminium ion cyclization reaction of readily accessible Baylis–Hillman derivatives and aldehydes in moderate to high yield. These new dihydropyrroles could be easily converted to pyrroles or pyrrolidines.

Substituent-directed reduction of cyclic aminals leading to two different heterocycles selectively: syntheses of functionalized nicotines and pyrido[2,3-b]azepines

Co-reporter:Yuewei Zhang, Lianyou Zheng, Fengzhi Yang, Zhuoqi Zhang, Qun Dang, Xu Bai

Tetrahedron 2015 Volume 71(Issue 13) pp:1930-1939

Publication Date(Web):1 April 2015

DOI:10.1016/j.tet.2015.02.025

A new strategy of substituent-directed reductive ring-opening of aza-bridged pyridoazepine systems was designed and developed. The direction of the ring-opening is determined by the electron negativity of substituents attached to the nitrogen atoms. A plausible mechanism involving iminiums as the key intermediates to the two reaction pathways was proposed. The reductive cleavage reaction provides a convenient method to access novel 2-aminonicotine and pyrido[2,3-b]azepine derivatives.

A Cascade of Acid-Promoted C–O Bond Cleavage and Redox Reactions: From Oxa-Bridged Benzazepines to Benzazepinones

Co-reporter:Yuewei Zhang, Fengzhi Yang, Lianyou Zheng, Qun Dang, and Xu Bai

Organic Letters 2014 Volume 16(Issue 23) pp:6041-6043

Publication Date(Web):November 14, 2014

DOI:10.1021/ol502971e

A sequence of C–O bond cleavage and redox reactions in oxa-bridged azepines was realized under acid promoted conditions. This protocol provides an atom-economical and straightforward approach to access benzo[b]azepin-5(2H)-ones in high yields. The formal synthesis of tolvaptan was achieved by exploiting this new transformation.

On-Demand Selection of the Reaction Path from Imino DielsAlder to Ene-Type Cyclization: Synthesis of Epiminopyrimido[4,5-b]azepines

Co-reporter:Yuewei Zhang;Yue Zhu;Lianyou Zheng;Lian-Gang Zhuo;Fengzhi Yang;Qun Dang;Zhi-Xiang Yu

European Journal of Organic Chemistry 2014 Volume 2014( Issue 3) pp:660-669

Publication Date(Web):

DOI:10.1002/ejoc.201301318

Abstract

Controlling the mode of reaction of a reactive intermediate such as an imine or iminium ion should enable the on-demand selection of the final products from the same starting materials. The successful execution of such a strategy will reduce the time required to prepare diverse scaffolds. The imines derived from 4-(allylamino)pyrimidine-5-carbaldehydes and anilines undergo Diels–Alder reactions to give pyrimido[4,5-h][1,6]naphthyridines in high yields. A complete switch from the intramolecular aza-Diels–Alder (IADA) path to an ene-type cyclization reaction was achieved by simply adjusting the reaction conditions (amount of acid catalyst, solvent, and temperature). This newly introduced ene-type cyclization reaction was used to prepare a series of epiminopyrimido[4,5-b]azepines. To gain insight into the mechanism of the two reaction pathways, a DFT study was carried out. Theoretical calculations showed that under acidic conditions an iminium intermediate favors the low-energy IADA pathway, which proceeds in a [4⁺ + 2] fashion. When acid is absent, the neutral imine intermediate favors the thermal ene-type cyclization reaction, which takes place by transfer of an allylic proton from the allylic amine to imine, followed by a barrierless nucleophilic addition process between the in-situ-generated anionic allylic amine and iminium ion. Amine addition to the alkene finally gives the epiminopyrimido[4,5-b]azepines.

Synthesis of novel 3-aryl isoindolinone derivatives

Co-reporter:Chen-ming Hu;Lian-you Zheng;Ya-zhong Pei

Chemical Research in Chinese Universities 2013 Volume 29( Issue 3) pp:487-494

Publication Date(Web):2013 June

DOI:10.1007/s40242-013-2294-5

A library of novel 3-aryl isoindolinone derivatives with aromatic amino acid derivative fragments was designed and synthesized. Two synthetic routes were employed to construct 3-aryl isoindolinone ring system for different amino acid derivatives.

Synthesis of novel 4H-pyrimido[1,6-a]pyrimidines via a one-pot three-component condensation

Co-reporter:Jinbao Xiang;Hanghang Li;Kai Yang;Lang Yi;Yongnan Xu;Qun Dang

Molecular Diversity 2012 Volume 16( Issue 1) pp:173-181

Publication Date(Web):2012 February

DOI:10.1007/s11030-011-9345-y

Highly substituted novel 4H-pyrimido[1,6-a] pyrimidines were prepared by a trifluoromethanesulfonic acid catalyzed one-pot three-component condensation of 4-aminopyrimidines, aldehydes, and β-ketoesters. A preliminary feasibility study was undertaken on these compounds, to assess the potential production of a library of further diversified compounds by nucleophilic replacement of Cl (R1) or by reaction of electrophiles with the NH2 (R2) group.

Synthesis of novel 6,7-dihydro-5H-pyrimido[4,5-e][1,4]diazepin-8(9H)-ones

Co-reporter:Jinbao Xiang;Xiaowei Hu;Qun Dang

Journal of Heterocyclic Chemistry 2011 Volume 48( Issue 5) pp:1091-1094

Publication Date(Web):

DOI:10.1002/jhet.615

Abstract

A new method was developed for the synthesis of 6,7-dihydro-5H-pyrimido[4,5-e][1,4]diazepin-8(9H)-one derivatives. The key to construct the pyrimido[4,5-e][1,4]diazepine core is the intramolecular amidation of N-((4-amino-6-chloropyrimidin-5-yl)methyl)-substituted amino acid esters. This methodology was validated through the preparation of 13 representative 6,7-dihydro-5H-pyrimido[4,5-e][1,4]diazepin-8(9H)-ones in moderate to good yields. J. Heterocyclic Chem., (2011).

Synthesis of highly substituted 2,3-dihydropyrimido[4,5-d]pyrimidin-4(1H)-ones from 4,6-dichloro-5-formylpyrimidine, amines and aldehydes

Co-reporter:Jinbao Xiang;Chao Geng;Lang Yi;Qun Dang

Molecular Diversity 2011 Volume 15( Issue 4) pp:839-847

Publication Date(Web):2011 November

DOI:10.1007/s11030-011-9314-5

A practical strategy was developed for the preparation of highly substituted 2,3-dihydropyrimido[4,5-d]pyrimidin-4(1H)-ones from 4,6-dichloro-5-formylpyrimidine, primary amines, and aldehydes. The key step for this synthesis entails a cyclization reaction involving an intramolecular amide addition to an iminium intermediate formed in situ from 4-amino-pyrimidine-5-carboxamide 2 and aldehydes to form the pyrimido[4,5-d]pyrimidine core with a strategically placed 5-Cl group for further derivatization. The utility of this methodology was demonstrated through the preparation of a 27-membered library of representative 2,3-dihydropyrimido[4,5-d]pyrimidin-4(1H)-ones in moderate to good yields.

Synthesis of Novel 8,9-Dihydro-5H-pyrimido[4,5-e][1,4]diazepin-7(6H)-ones

Co-reporter:Jinbao Xiang, Dongsheng Wen, Hongxiang Xie, Qun Dang and Xu Bai

ACS Combinatorial Science 2010 Volume 12(Issue 4) pp:503

Publication Date(Web):May 27, 2010

DOI:10.1021/cc100039w

Practical and efficient methods have been developed for the synthesis of 4,6,8,9-tetrasubstituted 8,9-dihydro-5H-pyrimido[4,5-e][1,4]diazepin-7(6H)-ones from 4,6-dicholoropyrimidine aldehyde, N-substituted amino acid esters, and amines in five steps. This synthetic strategy is based on suitably substituted pyrimidines as bis-electrophilic species reacting with various amines to construct the pyrimido[4,5-e][1,4]diazepine core with a strategically anchored functional group for further derivatization. The utility of this methodology was demonstrated through the preparation of a 33-membered library of representative 8,9-dihydro-5H-pyrimido[4,5-e][1,4]diazepin-7(6H)-ones in good to excellent yields.

Synthesis of Hexahydrobenzo[b]pyrimido[4,5-h][1,6]naphthyridines via an Intramolecular Hetero-Diels−Alder Reaction

Co-reporter:Fengzhi Yang, Lianyou Zheng, Jinbao Xiang, Qun Dang and Xu Bai

ACS Combinatorial Science 2010 Volume 12(Issue 4) pp:476

Publication Date(Web):June 15, 2010

DOI:10.1021/cc100018b

Method development was completed for a strategy to access a novel pyrimidine-fused heterocyclic scaffold. The key step for this synthetic route entails an intramolecular inverse electron demand hetero-Diels−Alder reaction of imines or iminiums formed in situ from allylaminopyrimidinealdehydes 3 and anilines. The reactions provided exclusively cis-configuration products 6. Products 6 were readily precipitated in the reaction solution in good to excellent yields. Further transformations of the phenylthio group were demonstrated by an oxidation and subsequent nucleophilic substitution sequence. The synthetic strategy provides an efficient way to access libraries of the tetracyclic pyrimidine-fused heterocycles that can be explored for potential pharmaceutical or biological activities.

Synthesis of novel tricyclic 4-chloro-7,8,10,11-tetrahydro-5H-benzo[e]pyrimido[4,5-b][1,4]diazepin-9(6H)-ones

Co-reporter:Jinbao Xiang;Lianyou Zheng;Tong Zhu;Qun Dang

Journal of Heterocyclic Chemistry 2010 Volume 47( Issue 4) pp:990-993

Publication Date(Web):

DOI:10.1002/jhet.384

Stereochemistry as a Tool in Deciphering the Processes of a Tandem Iminium Cyclization and Smiles Rearrangement

Co-reporter:Jinbao Xiang, Tong Zhu, Qun Dang, and Xu Bai

The Journal of Organic Chemistry 2010 Volume 75(Issue 23) pp:8147-8154

Publication Date(Web):November 9, 2010

DOI:10.1021/jo101798p

To understand the detailed mechanism of a recently reported tandem iminium cyclization and Smiles rearrangement, the reaction processes of a chiral substrate were investigated by monitoring its stereochemical courses. Under the tandem reaction conditions, chiral aldehyde 1 derived from l-prolinol led to two surprising results. First, the iminium cyclization gave a diastereomeric mixture with the cis-configured product as the predominant one. Second, Smiles rearrangement of both cis- and trans-2 led to the same product 3a directly derived from the trans isomer. The former was rationalized by the postulation of a Cram’s chelate transition state leading to the cis product as kinetically favored. The latter was due to the equilibration between the trans/cis pair involving a carbocation intermediate and the steric hindrance, which prevented the cis isomer from undergoing the intramolecular nucleophilic substitution. This hypothesis was further supported by the results of a competition experiment in which the addition of 1 equiv of p-methoxyaniline in the rearrangement step led to a significant amount of anilinyl-exchanged rearrangement product.

An efficient method to prepare 4-aminoquinazolines: Potential application to conformation-restricted bleomycin analogs

Co-reporter:Zhonglin Wei;Lianyou Zheng;Qun Dang

Journal of Heterocyclic Chemistry 2009 Volume 46( Issue 6) pp:1425-1429

Publication Date(Web):

DOI:10.1002/jhet.238

Method Development for a Pyridobenzodiazepine Library with Multiple Diversification Points

Co-reporter:Fuqiang Shi, Xianxiu Xu, Lianyou Zheng, Qun Dang and Xu Bai

ACS Combinatorial Science 2008 Volume 10(Issue 2) pp:158

Publication Date(Web):February 9, 2008

DOI:10.1021/cc7002039

Ezetimibe analogs with a reorganized azetidinone ring: Design, synthesis, and evaluation of cholesterol absorption inhibitions

Co-reporter:Xianxiu Xu, Renzhong Fu, Jin Chen, Shengwu Chen, Xu Bai

Bioorganic & Medicinal Chemistry Letters 2007 Volume 17(Issue 1) pp:101-104

Publication Date(Web):1 January 2007

DOI:10.1016/j.bmcl.2006.09.078

The underlying principle of drug design in this paper is that the maximum retention of the functional groups that exist in the marketed drug would provide a higher probability for comparable safety while the conformational changes in the newly created analogs should not constitute a significant structural variation to adversely affect biological activity. Four individual isomers of backbone re-organized ezetimibe analogs were designed and synthesized. Their effects on the cholesterol levels in rat serum were evaluated by a high-cholesterol and high-fat diet feeding experiment. All the new analogs showed significant effect in lowering the levels of total cholesterol in serum.Four individual isomers of backbone re-organized ezetimibe analogs were designed, synthesized, and evaluated for cholesterol absorption inhibition in rats.

The p38 MAPK inhibitor JLU1124 inhibits the inflammatory response induced by lipopolysaccharide through the MAPK-NF-κB pathway in RAW264.7 macrophages

Co-reporter:Xiao-ning Li, Jing Su, Lu Zhao, Jing-bao Xiang, Wanhe Wang, Fei Liu, Hong-yan Li, Jia-teng Zhong, Xu Bai, Lian-kun Sun

International Immunopharmacology (November 2013) Volume 17(Issue 3) pp:785-792

Publication Date(Web):1 November 2013

DOI:10.1016/j.intimp.2013.09.001

•Our results showed that a potent p38 MAPK inhibitor, JLU1124, can inhibit p38 phosphorylation efficiently.•Compared to the classic p38 MAPK inhibitor SB203580, JLU1124 inhibits p38 phosphorylation at low concentrations.•We discovered the significantly inhibitions of JLU1124 on cytokines in LPS-stimulated RAW264.7 macrophages.•We determined JLU1124 have anti-inflammatory action by inhibit p38MAPK/Akt/NF-κB pathway.Our previous results showed that JLU1124 is a potent p38 mitogen-activated protein kinase (MAPK) inhibitor. Compared to the classic p38 MAPK inhibitor SB203580, JLU1124 inhibits p38 phosphorylation at low concentrations without cytotoxicity on cells. p38 MAPK is a known target for inflammation treatment. Thus, we became interested in whether JLU1124 has anti-inflammatory effects. We used LPS stimulated RAW264.7 macrophages as a model of inflammation to evaluate the anti-inflammatory effects of JLU1124. Our results showed that p38 phosphorylation, the production of nitric oxide (NO), interleukin (IL)-6 and tumor necrosis factor (TNF)-α, the mRNA and protein levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 were enhanced by lipopolysaccharide (LPS). At concentrations of less than 10 μmol/L, JLU1124 inhibits p38 phosphorylation in a dose-dependent manner and significantly suppresses LPS-induced production of NO, IL-6 and TNF-α, and decreases the expressions of iNOS and COX-2 in RAW264.7 macrophages which indicate that JLU1124 has anti-inflammatory effects. However, JLU1124 has no significant effect on the phosphorylation of extracellular signal-regulated kinase1/2 and c-Jun NH2-terminal kinase which was involved in inflammation. Furthermore, our results showed that JLU1124 inhibits NF-κB inhibitor (IκB)α phosphorylation, nuclear translocation and transcriptional activity of NF-κB induced by LPS which may be through suppression of Akt phosphorylation. In conclusion, our study indicates that JLU1124 efficiently inhibits p38 phosphorylation and has anti-inflammatory effects in LPS-treated RAW264.7 macrophages. The anti-inflammatory mechanism of JLU1124 is mainly through decreasing Akt phosphorylation and inhibiting IκBα phosphorylation, thus suppressing NF-κB activation and nuclear translocation.