GuiSen Zhao

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Name: 赵桂森; GuiSen Zhao

Organization: Shandong University

Department: School of Pharmaceutical Sciences

Title: Professor

Chemicals
References

Structural optimization elaborates novel potent Akt inhibitors with promising anticancer activity

Co-reporter:Yang Liu, Yanzhen Yin, Zhen Zhang, Carrie J. Li, Hui Zhang, Daoguang Zhang, Changying Jiang, Krystle Nomie, Liang Zhang, Michael L. Wang, Guisen Zhao

European Journal of Medicinal Chemistry 2017 Volume 138(Volume 138) pp:

Publication Date(Web):29 September 2017

DOI:10.1016/j.ejmech.2017.06.067

•Pyrrolopyrimidine based phenylpiperidine carboxamides as potent Akt inhibitors.•Antiproliferative effects in mantle cell lymphoma cell lines and patient cells.•Induced cell apoptosis and cell cycle arrest in G2/M phase.•Downregulated the phosphorylation of Akt downstream effector GSK3β and S6.Targeting of Akt has been validated as a well rationalized approach to cancer treatment, and represents a promising therapeutic strategy for aggressive hematologic malignancies. We describe herein an exploration of novel Akt inhibitors for cancer therapy through structural optimization of previously described 4-(piperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine derivatives. Our studies yielded a novel series of pyrrolopyrimidine based phenylpiperidine carboxamides capable of potent inhibition of Akt1. Notably, 10h exhibited robust antiproliferative effects in both mantle cell lymphoma cell lines and primary patient tumor cells. Low micromolar doses of 10h induced cell apoptosis and cell cycle arrest in G2/M phase, and significantly downregulated the phosphorylation of Akt downstream effectors GSK3β and S6 in Jeko-1 cells.Structural optimization produced a novel series of pyrrolopyrimidine based phenylpiperidine carboxamides as potent Akt inhibitors. Notably, 10h exhibited robust antiproliferative effects in both mantle cell lymphoma cell lines and primary patient tumor cells.Download high-res image (180KB)Download full-size image

Discovery of 4-(Piperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine Derivatives as Akt Inhibitors

Co-reporter:Yang Liu;Yanzhen Yin;Jingya Zhang;Krystle Nomie;Liang Zhang;Dezhi Yang;Michael L. Wang

Archiv der Pharmazie 2016 Volume 349( Issue 5) pp:356-362

Publication Date(Web):

DOI:10.1002/ardp.201500427

A series of 4-(piperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine derivatives was synthesized and evaluated as Akt inhibitors by optimization of a weak screening lead (1). Typically, compounds 5q and 5t significantly improved the Akt1 inhibitory potency with IC₅₀ values of 18.0 and 21.3 nM, respectively, with desirable antiproliferative effect against the cell lines LNCaP and PC-3. The inhibitors 5q and 5t might serve as lead compounds for further exploration of Akt inhibitors as anticancer agents.

Development of anti-angiogenic tyrosine kinases inhibitors: molecular structures and binding modes

Co-reporter:Jingya Zhang;Yuanyou Wang;Linna Zhang;Guisen Zhao

Cancer Chemotherapy and Pharmacology 2016 Volume 77( Issue 5) pp:905-926

Publication Date(Web):2016/05/01

DOI:10.1007/s00280-016-2961-6

Since the hypothesis that solid tumors cause angiogenesis by secreting pro-angiogenic factors was introduced, research on angiogenesis has proceeded continuously. Development of inhibitors targeting the angiogenic tyrosine kinases, to block downstream signal transduction pathways, has become an important approach to cancer therapy. Our goal was to study the development and mechanism of anti-angiogenic tyrosine kinases inhibitors.We researched data on discovery of the inhibitors and their binding modes using the PubMed, Web of Science, Food and Drug Administration (FDA), and Clinical Trials Web sites.In the last decade, many small molecule inhibitors targeting angiogenesis have been designed and synthesized with many now entering the clinic or gaining FDA approval. Advances in understanding regulatory mechanisms of angiogenesis have enabled development of these drugs. The development of inhibitors up to Phase 3 clinical trials and, for many, FDA approval has helped leading to the discovery of additional compounds. The structures, activities, and binding modes of these inhibitors are discussed in this review.Though the angiogenesis inhibitors have different chemical structures, they share similar binding modes. Their interactions with the hinge region of receptor tyrosine kinases (RTKs) are critical to their effectiveness as inhibitors. In addition, as we review here, different drugs, when bound, induce different conformations of RTKs.

Recent Developments in Androgen Receptor Antagonists

Co-reporter:Fansheng Ran;Hualu Xing;Yang Liu;Daoguang Zhang;Pengzhan Li

Archiv der Pharmazie 2015 Volume 348( Issue 11) pp:757-775

Publication Date(Web):

DOI:10.1002/ardp.201500187

The androgen receptor (AR), a ligand-dependent transcription factor that regulates the expression of a series of downstream target genes after the binding of androgens, has been a target for the discovery of drugs used to treat prostate cancer. Prostate cancer always progresses to castration-resistant prostate cancer after a period of androgen deprivation therapy. Thus, developing potent androgen receptor antagonists for the therapy of castration-resistant prostate cancer possesses great significance. This review summarizes the preclinical development of androgen receptor antagonists, conventional androgen receptor antagonists that competitively bind to the ligand binding domain of the androgen receptor and coactivator antagonists of the androgen receptor, including both activation function-2 antagonists and binding function-3 antagonists. We hope that this review can help other researchers find new scaffolds and sites for the treatment of prostate cancer.

Design, synthesis and evaluation of novel indole derivatives as AKT inhibitors

Co-reporter:Dezhi Yang, Peng Wang, Jianzhen Liu, Hualu Xing, Yang Liu, Wencheng Xie, Guisen Zhao

Bioorganic & Medicinal Chemistry 2014 Volume 22(Issue 1) pp:366-373

Publication Date(Web):1 January 2014

DOI:10.1016/j.bmc.2013.11.022

Herein, we describe the discovery and synthesis of a new series of 1,2,4,7-tetra-substituted indole derivatives as novel AKT inhibitors by optimization of a weak hit methyl 4-(2-aminoethoxy)-1H-indole-2-carboxylate (1). Both representative compounds 6a and 6o exhibited the most potent inhibitory activities against AKT1, with inhibition rates of 72.5% and 78.6%, respectively, at concentrations of 10 nM. In addition, compounds 6a and 6o also potently inhibited the phosphorylation of the downstream GSK3 protein and displayed slightly better anti-proliferative activities in a prostate cancer cell line.

Design and discovery of 5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxamide inhibitors of HIV-1 integrase

Co-reporter:Daoguang Zhang, Bikash Debnath, Shenghui Yu, Tino Wilson Sanchez, Frauke Christ, Yang Liu, Zeger Debyser, Nouri Neamati, Guisen Zhao

Bioorganic & Medicinal Chemistry 2014 22(19) pp: 5446-5453

Publication Date(Web):

DOI:10.1016/j.bmc.2014.07.036

Design and synthesis of novel pyrimidone analogues as HIV-1 integrase inhibitors

Co-reporter:Shenghui Yu, Tino Wilson Sanchez, Yang Liu, Yanzhen Yin, Nouri Neamati, Guisen Zhao

Bioorganic & Medicinal Chemistry Letters 2013 Volume 23(Issue 22) pp:6134-6137

Publication Date(Web):15 November 2013

DOI:10.1016/j.bmcl.2013.09.018

A series of novel pyrimidone analogues have been designed and synthesized as HIV-1 integrase (IN) inhibitors. This study demonstrated that introducing a substituent in the N1-position of the pyrimidone scaffold does not significantly influence IN inhibitory activity. Molecular docking studies showed these compounds could occupy the IN active site and form pi–pi interactions with viral DNA nucleotides DC16 and DA17 to displace reactive viral DNA 3′OH and block intasome activity.A series of novel pyrimidone analogues were designed and synthesized as HIV-1 integrase inhibitors.

Thiadiazolea Promising Structure in Medicinal Chemistry

Co-reporter:Yijing Li;Jingkun Geng;Yang Liu;Shenghui Yu ; Guisen Zhao

ChemMedChem 2013 Volume 8( Issue 1) pp:27-41

Publication Date(Web):

DOI:10.1002/cmdc.201200355

Abstract

Many compounds containing a five-membered heterocyclic ring display exceptional chemical properties and versatile biological activities. In this Minireview, thiadiazoles are summarized according to their therapeutic potential, highlighting the versatility of this scaffold in medicinal chemistry. The unique properties of thiadiazoles are also discussed in relation to their potential effect on activity. Thiadiazole is a bioisostere of pyrimidine and oxadiazole, and given the prevalence of pyrimidine in nature it is unsurprising that thiadiazoles exhibit significant therapeutic potential. The sulfur atom of the thiadiazole imparts improved liposolubility, and the mesoionic nature of thiadiazoles makes these compounds better able to cross cellular membranes. By summarizing the thiadiazole-containing compounds reported in recent decades, we aim to give a brief introduction to their synthesis and diverse biological activities, such as anti-inflammatory, anticancer, antibacterial, antifungal, antiviral, antiparasitic, anticonvulsant, anticoagulant, antidiabetic, and to show the significant utility of the thiadiazole scaffolds in medicinal chemistry.

Design and synthesis of hydrazine and oxadiazole-containing derivatives of Sorafenib as antitumor agents

Co-reporter:Yuan-you Wang;Jian-zhen Liu;Xiao-yue Yu

Chemical Research in Chinese Universities 2013 Volume 29( Issue 3) pp:454-459

Publication Date(Web):2013 June

DOI:10.1007/s40242-013-2490-3

A series of hydrazine and oxadiazole analogs of Sorafenib was designed, synthesized and characterized by proton nuclear magnetic resonance(1H NMR) spectrometry and high resolution mass spectrometry(HRMS). The antiproliferative activities of these compounds against human colorectal carcinoma(HCT-116) and human breast cancer (MDA-MB-231) tumor cell lines were evaluated in vitro by MTT method[MTT=3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide]. The bioassay results suggest that most of the synthesized compounds have antitumor potential to HCT-116 cell line compared with MDA-MB-231 cell line. Compounds 8a, 8b, 8d, 8e, 9f and 9j competitive with Sorafenib demonstrated antiproliferative activities on HCT-116 cell line.

The synthesis of ethacrynic acid thiazole derivatives as glutathione S-transferase pi inhibitors

Co-reporter:Ting Li, Guyue Liu, Hongcai Li, Xinmei Yang, Yongkui Jing, Guisen Zhao

Bioorganic & Medicinal Chemistry 2012 Volume 20(Issue 7) pp:2316-2322

Publication Date(Web):1 April 2012

DOI:10.1016/j.bmc.2012.02.011

Glutathione S-transferase pi (GSTpi) is a phase II enzyme which protects cells from death and detoxifies chemotherapeutic agents in cancer cells. Ethacrynic acid (EA) is a weak GSTpi inhibitor. Structure modifications were done to improve the ability of EA to inhibit GSTpi activity. Eighteen EA thiazole derivatives were designed and synthesized. Compounds 9a, 9b and 9c with a replacement of carboxyl group of EA by a heterocyclic thiazole exhibited improvement over EA to inhibit GSTpi activity.

Novel Oxadiazole Analogues Derived from Ethacrynic Acid: Design, Synthesis, and Structure−Activity Relationships in Inhibiting the Activity of Glutathione S-Transferase P1-1 and Cancer Cell Proliferation

Co-reporter:Xinmei Yang ; Guyue Liu ; Hongcai Li ; Yun Zhang ; Dandan Song ; Chunmin Li ; Rui Wang ; Bo Liu ; Wen Liang ; Yongkui Jing

Journal of Medicinal Chemistry 2010 Volume 53(Issue 3) pp:1015-1022

Publication Date(Web):January 7, 2010

DOI:10.1021/jm9011565

Ethacrynic acid (EA) is a glutathione S-transferase P1-1 (GST P1-1) inhibitor with weak antiproliferative ability in tumor cells. By use of the principle of bioisosterism, a series of novel EA oxadiazole analogues were designed and synthesized. The structure−activity relationships of inhibiting GST P1-1 activity and cell proliferation of those EA analogues were investigated in human leukemia HL-60 cells. Our data revealed that those EA oxadiazole analogues had improved antiproliferative activity and most of them had similar or better inhibitory effects on GST P1-1 activity than EA. Compound 6u was one of the potent antiproliferative agents without inhibition of GST P1-1 activity. Compounds 6r and 6s were two potent cell growth inhibitors in several solid tumor cell lines with the concentrations inhibiting half of cell growth of less than 5 μM. Our data suggest that these EA oxadiazole analogues are promising antitumor agents that may act through GST P1-1 inhibition-dependent and/or -independent pathways.

Developments in Nonsteroidal Antiandrogens Targeting the Androgen Receptor

Co-reporter:Bo Liu;Lei Su;Jingkun Geng;Junjie Liu; Guisen Zhao

ChemMedChem 2010 Volume 5( Issue 10) pp:1651-1661

Publication Date(Web):

DOI:10.1002/cmdc.201000259

Amide-containing diketoacids as HIV-1 integrase inhibitors: Synthesis, structure–activity relationship analysis, and biological activity

Co-reporter:Hongcai Li, Chao Wang, Tino Sanchez, Yanmei Tan, Chunying Jiang, Nouri Neamati, Guisen Zhao

Bioorganic & Medicinal Chemistry 2009 Volume 17(Issue 7) pp:2913-2919

Publication Date(Web):1 April 2009

DOI:10.1016/j.bmc.2009.01.077

HIV-1 integrase, which catalyzes the integration of the viral genome into the cellular chromosome, is an essential enzyme for retroviral replication, and represents an attractive and validated target in the development of therapeutics against AIDS. In this paper, 17 amide-containing novel diketoacids were designed and synthesized, and their ability to inhibit HIV-1 integrase was tested. The structure–activity relationships were also analyzed.A series of novel amide-containing diketoacids were designed and synthesized to develop potent HIV integrase inhibitors. Their inhibition of HIV integrase was tested and the structure–activity relationships were discussed.

Design and synthesis of novel nitrogen-containing polyhydroxylated aromatics as HIV-1 integrase inhibitors from caffeic acid phenethyl ester

Co-reporter:Peng Wang, Chuan Liu, Tino Sanches, Yuan Zhong, Bo Liu, Junlong Xiong, Nouri Neamati, Guisen Zhao

Bioorganic & Medicinal Chemistry Letters 2009 Volume 19(Issue 16) pp:4574-4578

Publication Date(Web):15 August 2009

DOI:10.1016/j.bmcl.2009.06.100

A series of nitrogen-containing polyhydroxylated aromatics from caffeic acid phenethyl ester were designed and synthesized as HIV-1 integrase inhibitors. Most of these compounds exhibited potent inhibitory activities at micromolar concentrations against HIV-1 integrase in the 3′-end processing and the strand transfer. Their key structure–activity relationship was also discussed.A series of novel nitrogen-containing polyhydroxylated aromatics were evaluated for their ability to inhibit HIV-1 integrase at micromolar concentrations.

Caffeoyl naphthalenesulfonamide derivatives as HIV integrase inhibitors

Co-reporter:Yu-Wen Xu, Gui-Sen Zhao, Cha-Gyun Shin, Heng-Chang Zang, Chong-Kyo Lee, Yong Sup Lee

Bioorganic & Medicinal Chemistry 2003 Volume 11(Issue 17) pp:3589-3593

Publication Date(Web):15 August 2003

DOI:10.1016/S0968-0896(03)00372-9

HIV-1 integrase (IN) is an essential enzyme for retroviral replication and a rational target for the design of anti-AIDS drugs. In the present study, we have designed, synthesized and tested a series of caffeoyl naphthalenesulfonamide derivatives as HIV integrase inhibitors. Among these compounds, we found that HIV integrase inhibitory activities of compounds III-3 and III-4 were more potent than l-chicoric acid (IC50=11.8 μg/mL) and others were comparable to l-chicoric acid. Furthermore, the structure–activity relationships of these compounds were studied. The information gathered from this paper will be useful in the development and design of HIV-1 integrase inhibitors in the future.A series of caffeoylnaphfhalenesulonaminde derivatives have been synthesized and the anti-HIV IN activities were described.