Three-dimensional quantitative structure activity relationship （3D-QSAR） and docking studies of a series of arylthioindole derivatives as tubulin inhibitors against human breast cancer cell line MCF-7 have been carr...Three-dimensional quantitative structure activity relationship （3D-QSAR） and docking studies of a series of arylthioindole derivatives as tubulin inhibitors against human breast cancer cell line MCF-7 have been carried out. An optimal 3D-QSAR model from the comparative molecular field analysis （CoMFA） for training set with significant statistical quality （R2=0.898） and predictive ability （q2=0.654） was established. The same model was further applied to predict pIC50 values of the compounds in test set, and the resulting predictive correlation coefficient R2（pred） reaches 0.816, further showing that this CoMFA model has high predictive ability. Moreover, the appropriate binding orientations and conformations of these compounds interacting with tubulin are located by docking study, and it is very interesting to find the consistency between the CoMFA field distribution and the 3D topology structure of active site of tubulin. Based on CoMFA along with docking results, some important factors improving the activities of these compounds were discussed in detail and were summarized as follows： the substituents R3-R5 （on the phenyl ring） with higher electronegativity, the substituent R6 with higher eleetropositivity and bigger bulk, the substituent R7 with smaller bulk, and so on. In addition, five new compounds with higher activities have been designed. Such results can offer useful theoretical references for experimental works.展开更多
Mornaphthoate E(MPE)is a prenylated naphthoic acid methyl ester isolated from the roots of a famous Chinese medicinal plant Morinda officinalis and shows remarkable cytotoxicity against several human tumor cell lines....Mornaphthoate E(MPE)is a prenylated naphthoic acid methyl ester isolated from the roots of a famous Chinese medicinal plant Morinda officinalis and shows remarkable cytotoxicity against several human tumor cell lines.In the current project,the first total synthesis of(±)-MPE was achieved in seven steps and 5.6%overall yield.Then the in vitro anti-tumor activity of MPE was first assessed for both enantiomers in two breast cancer cells,with the levoisomer exerting slightly better potency.The in vivo anti-tumor effect was further verified by applying the racemate in an orthotopic autograft mouse model.Notably,MPE exerted promising anti-metastasis activity both in vitro and in vivo and showed no obvious toxicity on mice at the therapeutic dosage.Mechanistic investigations demonstrated that MPE acted as a tubulin polymerization stabilizer and disturbed the dynamic equilibrium of microtubules via regulating PI3K/Akt signaling.In conclusion,our work has provided a new chemical template for the future design and development of next-generation tubulin-targeting chemotherapies.展开更多
A series of new combretastatin-A4 analogs were synthesized, in which a six-membered ring connects the linking bridge and A ring, and their tumor cell growth and tubulin-polymerization inhibitory activity were evaluate...A series of new combretastatin-A4 analogs were synthesized, in which a six-membered ring connects the linking bridge and A ring, and their tumor cell growth and tubulin-polymerization inhibitory activity were evaluated. These compounds appear to be potential tubulin-polymerization inhibitors, Compounds 1b with amino substituted on position 3 of B ring conferred optimal bioactivity, higher than that of the lead compound 22b and equivalent to that of CA-4. The binding modes of these compounds to tuhulin were obtained by molecular docking, which can explain the structure-activity relationship. The studies presented here provide a new structural type for the development of novel antitumor agents.展开更多
Antibody-drug conjugates(ADCs),which combine the advantages of monoclonal antibodies with precise targeting and payloads with efficient killing,show great clinical therapeutic value.The ADCs’payloads play a key role ...Antibody-drug conjugates(ADCs),which combine the advantages of monoclonal antibodies with precise targeting and payloads with efficient killing,show great clinical therapeutic value.The ADCs’payloads play a key role in determining the efficacy of ADC drugs and thus have attracted great attention in the field.An ideal ADC payload should possess sufficient toxicity,low immunogenicity,high stability,and modifiable functional groups.Common ADC payloads include tubulin inhibitors and DNA damaging agents,with tubulin inhibitors accounting for more than half of the ADC drugs in clinical development.However,due to clinical limitations of traditional ADC payloads,such as inadequate efficacy and the development of acquired drug resistance,novel highly efficient payloads with diverse targets and reduced side effects are being developed.This perspective summarizes the recent research advances of traditional and novel ADC payloads with main focuses on the structure-activity relationship studies,co-crystal structures,and designing strategies,and further discusses the future research directions of ADC payloads.This review also aims to provide valuable references and future directions for the development of novel ADC payloads that will have high efficacy,low toxicity,adequate stability,and abilities to overcome drug resistance.展开更多
Cancer,which is the uncontrolled growth of cells,is the second leading cause of death after heart disease.Targeting drugs,especially to specific genes and proteins involved in growth and survival of cancer cells,is th...Cancer,which is the uncontrolled growth of cells,is the second leading cause of death after heart disease.Targeting drugs,especially to specific genes and proteins involved in growth and survival of cancer cells,is the prime need of research world-wide.Indole moiety,which is a combination of aromatic-heterocyclic compounds,is a constructive scaffold for the development of novel leads.Owing to its bioavailability,high unique chemical properties and significant pharmacological behaviours,indole is considered as the most inquisitive scaffold for anticancer drug research.This is illustrated by the fact that the U.S.Food and Drug Administration(FDA)has recently approved several indole-based anticancer agents such as panobinostat,alectinib,sunitinib,osimertinib,anlotinib and nintedanib for clinical use.Furthermore,hundreds of studies on the synthesis and activity of the indole ring have been published in the last three years.Taking into account the facts stated above,we have presented the most recent advances in medicinal chemistry of indole derivatives,encompassing hot articles published between 2018and 2021 in anticancer drug research.The recent advances made towards the synthesis of promising indole-based anticancer compounds that may act via various targets such as topoisomerase,tubulin,apoptosis,aromatase,kinases,etc.,have been discussed.This review also summarizes some of the recent efficient green chemical synthesis for indole rings using various catalysts for the period during 2018—2021.The review also covers the synthesis,structure-activity relationship,and mechanism by which these leads have demonstrated improved and promising anticancer activity.Indole molecules under clinical and preclinical stages are classified into groups based on their cancer targets and presented in tabular form,along with their mechanism of action.The goal of this review article is to point the way for medicinal chemists to design and develop effective indole-based anticancer agents.展开更多
基金This work was supported by the National Natural Science Foundation of China （No.20673148）. We heartily thank the Molecular Discovery Ltd. for giving us the Dock 6.0 program as a freeware and the College of Life Sciences, Sun Yat-Sen University for the SYBYL 6.9 computation environment support.
文摘Three-dimensional quantitative structure activity relationship （3D-QSAR） and docking studies of a series of arylthioindole derivatives as tubulin inhibitors against human breast cancer cell line MCF-7 have been carried out. An optimal 3D-QSAR model from the comparative molecular field analysis （CoMFA） for training set with significant statistical quality （R2=0.898） and predictive ability （q2=0.654） was established. The same model was further applied to predict pIC50 values of the compounds in test set, and the resulting predictive correlation coefficient R2（pred） reaches 0.816, further showing that this CoMFA model has high predictive ability. Moreover, the appropriate binding orientations and conformations of these compounds interacting with tubulin are located by docking study, and it is very interesting to find the consistency between the CoMFA field distribution and the 3D topology structure of active site of tubulin. Based on CoMFA along with docking results, some important factors improving the activities of these compounds were discussed in detail and were summarized as follows： the substituents R3-R5 （on the phenyl ring） with higher electronegativity, the substituent R6 with higher eleetropositivity and bigger bulk, the substituent R7 with smaller bulk, and so on. In addition, five new compounds with higher activities have been designed. Such results can offer useful theoretical references for experimental works.
基金This project was financially supported by the National Natural Science Foundation of China(No.82073729,22225105).
文摘Mornaphthoate E(MPE)is a prenylated naphthoic acid methyl ester isolated from the roots of a famous Chinese medicinal plant Morinda officinalis and shows remarkable cytotoxicity against several human tumor cell lines.In the current project,the first total synthesis of(±)-MPE was achieved in seven steps and 5.6%overall yield.Then the in vitro anti-tumor activity of MPE was first assessed for both enantiomers in two breast cancer cells,with the levoisomer exerting slightly better potency.The in vivo anti-tumor effect was further verified by applying the racemate in an orthotopic autograft mouse model.Notably,MPE exerted promising anti-metastasis activity both in vitro and in vivo and showed no obvious toxicity on mice at the therapeutic dosage.Mechanistic investigations demonstrated that MPE acted as a tubulin polymerization stabilizer and disturbed the dynamic equilibrium of microtubules via regulating PI3K/Akt signaling.In conclusion,our work has provided a new chemical template for the future design and development of next-generation tubulin-targeting chemotherapies.
基金supported by the National Natural Science Foundation of China(Nos.21172260 and 30901859)Shanghai Natural Science Foundation(No.09ZR1438800)"Chen Guang" Project supported by Shanghai Municipal Education Commission and Shanghai Education Development Foundation(No.12CG42)
文摘A series of new combretastatin-A4 analogs were synthesized, in which a six-membered ring connects the linking bridge and A ring, and their tumor cell growth and tubulin-polymerization inhibitory activity were evaluated. These compounds appear to be potential tubulin-polymerization inhibitors, Compounds 1b with amino substituted on position 3 of B ring conferred optimal bioactivity, higher than that of the lead compound 22b and equivalent to that of CA-4. The binding modes of these compounds to tuhulin were obtained by molecular docking, which can explain the structure-activity relationship. The studies presented here provide a new structural type for the development of novel antitumor agents.
基金provided by the National Natural Science Foundation of China(82073318)the Fundamental Research Funds for the Central Universities(SCU2022D025,0082604151345,China)+1 种基金Sichuan Science and Technology Program Projects(2019YFS0003,China)to Yuxi Wangprovided by the University of Tennessee College of Pharmacy Drug Discovery Center to Wei Li。
文摘Antibody-drug conjugates(ADCs),which combine the advantages of monoclonal antibodies with precise targeting and payloads with efficient killing,show great clinical therapeutic value.The ADCs’payloads play a key role in determining the efficacy of ADC drugs and thus have attracted great attention in the field.An ideal ADC payload should possess sufficient toxicity,low immunogenicity,high stability,and modifiable functional groups.Common ADC payloads include tubulin inhibitors and DNA damaging agents,with tubulin inhibitors accounting for more than half of the ADC drugs in clinical development.However,due to clinical limitations of traditional ADC payloads,such as inadequate efficacy and the development of acquired drug resistance,novel highly efficient payloads with diverse targets and reduced side effects are being developed.This perspective summarizes the recent research advances of traditional and novel ADC payloads with main focuses on the structure-activity relationship studies,co-crystal structures,and designing strategies,and further discusses the future research directions of ADC payloads.This review also aims to provide valuable references and future directions for the development of novel ADC payloads that will have high efficacy,low toxicity,adequate stability,and abilities to overcome drug resistance.
基金the Managing Committee of Shivalik College of Pharmacy。
文摘Cancer,which is the uncontrolled growth of cells,is the second leading cause of death after heart disease.Targeting drugs,especially to specific genes and proteins involved in growth and survival of cancer cells,is the prime need of research world-wide.Indole moiety,which is a combination of aromatic-heterocyclic compounds,is a constructive scaffold for the development of novel leads.Owing to its bioavailability,high unique chemical properties and significant pharmacological behaviours,indole is considered as the most inquisitive scaffold for anticancer drug research.This is illustrated by the fact that the U.S.Food and Drug Administration(FDA)has recently approved several indole-based anticancer agents such as panobinostat,alectinib,sunitinib,osimertinib,anlotinib and nintedanib for clinical use.Furthermore,hundreds of studies on the synthesis and activity of the indole ring have been published in the last three years.Taking into account the facts stated above,we have presented the most recent advances in medicinal chemistry of indole derivatives,encompassing hot articles published between 2018and 2021 in anticancer drug research.The recent advances made towards the synthesis of promising indole-based anticancer compounds that may act via various targets such as topoisomerase,tubulin,apoptosis,aromatase,kinases,etc.,have been discussed.This review also summarizes some of the recent efficient green chemical synthesis for indole rings using various catalysts for the period during 2018—2021.The review also covers the synthesis,structure-activity relationship,and mechanism by which these leads have demonstrated improved and promising anticancer activity.Indole molecules under clinical and preclinical stages are classified into groups based on their cancer targets and presented in tabular form,along with their mechanism of action.The goal of this review article is to point the way for medicinal chemists to design and develop effective indole-based anticancer agents.
