To further expand an effective modified route for the shift from an antibacterial fluoroquinolone （FQ） to an antitumor FQ, two series of title compounds based on an isostere of the FQ C3 carboxylic group with two fu...To further expand an effective modified route for the shift from an antibacterial fluoroquinolone （FQ） to an antitumor FQ, two series of title compounds based on an isostere of the FQ C3 carboxylic group with two fused heterocyclic rings, [ 1,2,4]triazolo[3,4- b][1,3,4]thiadiazine and pyrazolo[5,1-c][1,2,4]triazole, respectively, were designed and synthesized starting from the current antibacterial FQs, and their in vitro antitumor activity against L1210, CHO cell lines were evaluated via their respective IC50 values.展开更多
Five C3/C3 fluoroquinolone dimers tethered with a fused heterocyclic ring of s-triazolo[2,1-b][1,3,4]thiadiazole derived from antibacterial quinoiones were synthesized and characterized,and their in vitro antitumor ac...Five C3/C3 fluoroquinolone dimers tethered with a fused heterocyclic ring of s-triazolo[2,1-b][1,3,4]thiadiazole derived from antibacterial quinoiones were synthesized and characterized,and their in vitro antitumor activity against L1210,CHO cell lines was evaluated via the respective IC_(50) values.展开更多
To further explore an efficient modified route for the shift from an antibacterial fluoroquinolone to an antitumor one,mono-Schiff bases 6a-6h related to ciprofloxacin C3 carbonylhydrazone and bis-Schiff bases 4a-4h c...To further explore an efficient modified route for the shift from an antibacterial fluoroquinolone to an antitumor one,mono-Schiff bases 6a-6h related to ciprofloxacin C3 carbonylhydrazone and bis-Schiff bases 4a-4h corresponding to C3/C7 carbonylhydrazone/hydrazone attached on a skeleton of ciprofloquinolone were designed and synthesized,and their in vitro antitumor activity against CHO,HL60,L1210 cells and antibacterial activity against Staphylococcus aureus and Escherichia coli were also reported.展开更多
Objectives:Immunomodulatory drugs(IMiDs),functioning as molecular glue degraders,have been approved for treating various hematological malignancies;however,the inevitable acquired drug resistance resulting from their ...Objectives:Immunomodulatory drugs(IMiDs),functioning as molecular glue degraders,have been approved for treating various hematological malignancies;however,the inevitable acquired drug resistance resulting from their skeletal similarity and hematological toxicities poses significant obstacles to their clinical treatment.The study aimed to develop degraders with potent efficiency and low toxicity.Methods:Phenotypic profiling,elaborate structure-activity relationships(SAR),rational drug design and degradation profiles investigations,quantitative proteomics analysis and cell-based functional studies,and pharmacokinetic studies were conducted to develop more potent degraders.Results:This study developed novel CRBN-binding moieties throughmethylene deletion in lenalidomide’s isoindole core.Lead compounds MGD-A7 and MGD-C9 demonstrated superior antiproliferative efficacy vs.IMiDs,with submicromolar potency.MGD-A7 and MGD-C9 significantly and selectively induced the degradation of Ikaros Family Zinc Finger Proteins 1 and 3(IKZF1/3)with nanomolar potency via a CRBN-dependent pathway.Mechanistically,MGD-A7 and MGD-C9 dramatically induced cell apoptosis and G1 cell cycle arrest and MGDC9 exhibited favorable pharmacokinetic properties in vivo.Furthermore,MGD-C9 exhibited significant synergistic effects with standard-of-care agents in various hematological malignancy cells.Conclusions:These results indicate that MGD-C9 could act as a highly effective CRBN ligand and is expected to become a candidate drug for the treatment of hematological malignancies.展开更多
To contribute to the development of an efficient method for the conversion of antibacterial fluoroquinolones to antitumor fluoroquinolones,a series of C3/C3 bis-fluoroquinolone fused heterocycles cross-linked with a[1...To contribute to the development of an efficient method for the conversion of antibacterial fluoroquinolones to antitumor fluoroquinolones,a series of C3/C3 bis-fluoroquinolone fused heterocycles cross-linked with a[1,2,4]-triazolo[3,4-b][1,3,4]-thiadiazole core as a common bioisostere of two carboxylic acid groups was designed and synthesized as their hydrochloride salts.Structures were characterized by elemental analysis and spectral data and their in vitro antitumor activity against L1210,CHO and HL60 cell lines was screened by determination of their IC50 values in the methylthiazole trazolium(MTT)assay.Two compounds were highly potent against the HL60 cell line and represent promising lead compounds for future development.展开更多
基金supported by National Natural Science Foundation of China(Nos.20872028,21072045)
文摘To further expand an effective modified route for the shift from an antibacterial fluoroquinolone （FQ） to an antitumor FQ, two series of title compounds based on an isostere of the FQ C3 carboxylic group with two fused heterocyclic rings, [ 1,2,4]triazolo[3,4- b][1,3,4]thiadiazine and pyrazolo[5,1-c][1,2,4]triazole, respectively, were designed and synthesized starting from the current antibacterial FQs, and their in vitro antitumor activity against L1210, CHO cell lines were evaluated via their respective IC50 values.
基金supported by National Natural Science Foundation of China(No.20872028)
文摘Five C3/C3 fluoroquinolone dimers tethered with a fused heterocyclic ring of s-triazolo[2,1-b][1,3,4]thiadiazole derived from antibacterial quinoiones were synthesized and characterized,and their in vitro antitumor activity against L1210,CHO cell lines was evaluated via the respective IC_(50) values.
基金supported by the National Natural Science Foundation of China(Nos20872028 and 21072045)
文摘To further explore an efficient modified route for the shift from an antibacterial fluoroquinolone to an antitumor one,mono-Schiff bases 6a-6h related to ciprofloxacin C3 carbonylhydrazone and bis-Schiff bases 4a-4h corresponding to C3/C7 carbonylhydrazone/hydrazone attached on a skeleton of ciprofloquinolone were designed and synthesized,and their in vitro antitumor activity against CHO,HL60,L1210 cells and antibacterial activity against Staphylococcus aureus and Escherichia coli were also reported.
基金supported by the National Natural Science Foundation of China(No.82404417)Key Project of North China University of Science and Technology(ZD-YG-202408)State Key Laboratory of National Security Specially Needed Medicines Program(No.LTMC2022ZZ006).
文摘Objectives:Immunomodulatory drugs(IMiDs),functioning as molecular glue degraders,have been approved for treating various hematological malignancies;however,the inevitable acquired drug resistance resulting from their skeletal similarity and hematological toxicities poses significant obstacles to their clinical treatment.The study aimed to develop degraders with potent efficiency and low toxicity.Methods:Phenotypic profiling,elaborate structure-activity relationships(SAR),rational drug design and degradation profiles investigations,quantitative proteomics analysis and cell-based functional studies,and pharmacokinetic studies were conducted to develop more potent degraders.Results:This study developed novel CRBN-binding moieties throughmethylene deletion in lenalidomide’s isoindole core.Lead compounds MGD-A7 and MGD-C9 demonstrated superior antiproliferative efficacy vs.IMiDs,with submicromolar potency.MGD-A7 and MGD-C9 significantly and selectively induced the degradation of Ikaros Family Zinc Finger Proteins 1 and 3(IKZF1/3)with nanomolar potency via a CRBN-dependent pathway.Mechanistically,MGD-A7 and MGD-C9 dramatically induced cell apoptosis and G1 cell cycle arrest and MGDC9 exhibited favorable pharmacokinetic properties in vivo.Furthermore,MGD-C9 exhibited significant synergistic effects with standard-of-care agents in various hematological malignancy cells.Conclusions:These results indicate that MGD-C9 could act as a highly effective CRBN ligand and is expected to become a candidate drug for the treatment of hematological malignancies.
基金supported by the National Natural Science Foundation of China(nos.20872028,21072045).
文摘To contribute to the development of an efficient method for the conversion of antibacterial fluoroquinolones to antitumor fluoroquinolones,a series of C3/C3 bis-fluoroquinolone fused heterocycles cross-linked with a[1,2,4]-triazolo[3,4-b][1,3,4]-thiadiazole core as a common bioisostere of two carboxylic acid groups was designed and synthesized as their hydrochloride salts.Structures were characterized by elemental analysis and spectral data and their in vitro antitumor activity against L1210,CHO and HL60 cell lines was screened by determination of their IC50 values in the methylthiazole trazolium(MTT)assay.Two compounds were highly potent against the HL60 cell line and represent promising lead compounds for future development.
