RESUMO
Monoamine oxidases A and B (MAO-A and MAO-B) play important roles in biogenic amine metabolism, oxidative stress, and chronic inflammation. Particularly, MAO-B selective inhibitors are promising therapeutic choices for the treatment of neurodegenerative diseases, such as Pakinson's disease and Alzheimer's disease. Herein, novel 3,6-disubstituted isobenzofuran-1(3H)-ones were designed, synthesized and evaluated in vitro as inhibitors of monoamine oxidases A and B. Structure-activity relationships were investigated, and all of the compounds with (R)-3-hydroxy pyrrolidine moiety on the 6-position displayed preferable inhibition toward the MAO-B isoform. Among them, compounds 6c with a 4'-fluorobenzyl ring and 6m bearing a 3',4'-difluorobenzyl ring on the 3-position were the most potent MAO-B inhibitors with IC50 values of 0.35 µM and 0.32 µM, respectively. The binding mode of compound 6m in MAO-B was predicted by CDOCKER program, revealing that (R)-3-hydroxypyrrolidine moiety is a critical structural feature for this series of MAO-B inhibitors. Compound 6m could serve as a new template structure for developing potent and selective MAO-B inhibitors.
Assuntos
Doença de Alzheimer , Monoaminoxidase , Doença de Alzheimer/tratamento farmacológico , Humanos , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/química , Relação Estrutura-AtividadeRESUMO
Pin1 is a peptidyl prolyl cis-trans isomerase (PPIase) and inhibiting Pin1 is a potential way for discovering anti-tumor agents. With an aim to find potent Pin1 inhibitors with a novel scaffold, a series of thiazole derivatives with an alicyclic heterocycles on the 2-position were designed, synthesized and tested against human Pin1. Compound 9p bearing a 2-oxa-6-azaspiro [3,3] heptane moiety on the thiazole scaffold was identified as the most potent Pin1 inhibitor of this series with an IC50 value of 0.95 µM. The structure-activity relationship (SAR) and molecular modeling study indicated that introducing an alicyclic ring with an H-bond acceptor would be a viable way to improve the binding affinity.
Assuntos
Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Peptidilprolil Isomerase de Interação com NIMA/antagonistas & inibidores , Tiazóis/farmacologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Modelos Moleculares , Estrutura Molecular , Peptidilprolil Isomerase de Interação com NIMA/genética , Peptidilprolil Isomerase de Interação com NIMA/metabolismo , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/químicaRESUMO
Novel quinazoline-2,4(1H,3H)-dione derivatives bearing a 3-amino pyrrolidine moiety were designed and synthesized as PARP-1/2 inhibitors. Structure-activity relationships were examined which revealed a number of potent PARP-1/2 inhibitors with moderate selectivity toward PARP-1 over PARP-2. These compounds had IC50 values against PARP-1 at the 10-9 M level and against PARP-2 at the 10-8 M level. Among all the synthesized compounds, compounds 10 and 11 displayed strong cytotoxicities which are either used as a single agent or in combination with temozolomide (TMZ) in MX-1 cells (10, IC50 < 3.12 µM, PF50 > 10; 11, IC50 = 3.02 µM, PF50 ≈ 10). In vivo tumor growth inhibition was investigated using compound 11 in combination with TMZ, and it was demonstrated that compound 11 could strongly potentiate the cytotoxicity of TMZ in a MX-1 xenograft tumor model. The co-crystal structure of compound 11 complexed with PARP-1 was achieved and demonstrated a unique binding mode.
Assuntos
Antineoplásicos/química , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Inibidores de Poli(ADP-Ribose) Polimerases/química , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Quinazolinas/química , Quinazolinas/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Desenho de Fármacos , Feminino , Humanos , Camundongos , Simulação de Acoplamento Molecular , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Poli(ADP-Ribose) Polimerase-1/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/síntese química , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Poli(ADP-Ribose) Polimerases/metabolismo , Quinazolinas/síntese química , Quinazolinas/farmacologia , Relação Estrutura-AtividadeRESUMO
Pin1 (Protein interacting with NIMA1) is a cis-trans isomerase and promotes the amide bond rotation of phosphoSer/Thr-Pro motifs in its substrates. Inhibition of Pin1 might be a novel strategy for developing anticancer agents. Herein, a series of pyrimidine derivatives were synthesized and their Pin1 inhibitory activities were evaluated. Among them, four compounds (2a, 2f, 2h and 2l) displayed potent inhibitory activities against Pin1 with IC50 values lower than 3⯵M. This series of pyrimidine-based inhibitors presented time-dependent inhibition against Pin1. The structure-activity relationships on the 2-, 4- and 5-positions of the pyrimidine ring were analyzed in details, which would facilitate further exploration of new Pin1 inhibitors.
Assuntos
Inibidores Enzimáticos/síntese química , Peptidilprolil Isomerase de Interação com NIMA/antagonistas & inibidores , Pirimidinas/química , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Humanos , Peptidilprolil Isomerase de Interação com NIMA/genética , Peptidilprolil Isomerase de Interação com NIMA/metabolismo , Ligação Proteica , Pirimidinas/síntese química , Pirimidinas/metabolismo , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/química , Proteínas Recombinantes/isolamento & purificação , Relação Estrutura-AtividadeRESUMO
The PARP-2 selective inhibitor is important for clarifying specific roles of PARP-2 in the pathophysiological process and developing desired drugs with reduced off-target side effects. In this work, a series of novel quinazoline-2,4(1H,3H)-dione derivatives was designed and synthesized to explore isoform selective PARP inhibitors. As a result, compound 11a (PARP-1 IC50=467nM, PARP-2 IC50=11.5nM, selectivity PARP-1/PARP-2=40.6) was disclosed as the most selective PARP-2 inhibitor with high potency to date. The binding features of compound 11a within PARP-1 and PARP-2 were investigated respectively to provide useful insights for the further construction of new isoform selective inhibitors of PARP-1 and PARP-2 by using CDOCKER program.
Assuntos
Descoberta de Drogas , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Poli(ADP-Ribose) Polimerases/efeitos dos fármacos , Quinazolinas/química , Quinazolinas/farmacologia , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Humanos , Concentração Inibidora 50 , Modelos Moleculares , Espectroscopia de Prótons por Ressonância Magnética , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
Pin1 (Protein interacting with NIMA1) is a peptidyl prolyl cis-trans isomerase (PPIase) which specifically catalyze the conformational conversion of the amide bond of pSer/Thr-Pro motifs in its substrate proteins and is a novel promising anticancer target. A series of new thiazole derivatives were designed and synthesized, and their inhibitory activities were measured against human Pin1 using a protease-coupled enzyme assay. Of all the tested compounds, a number of thiazole derivatives bearing an oxalic acid group at 4-position were found to be potent Pin1 inhibitors with IC50 values at low micromolar level. The detailed structure-activity relationships were analyzed and the binding features of compound 10b (IC50 5.38µM) was predicted using CDOCKER program. The results of this research would provide informative guidance for further optimizing thiazole derivatives as potent Pin1 inhibitors.
Assuntos
Inibidores Enzimáticos/farmacologia , Peptidilprolil Isomerase de Interação com NIMA/antagonistas & inibidores , Tiazóis/farmacologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Modelos Moleculares , Estrutura Molecular , Peptidilprolil Isomerase de Interação com NIMA/metabolismo , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/químicaRESUMO
Fourteen new compounds with 2,3-dihydro-1H-pyrrolo[3,2-c]-quinoline or 2,3,5,9b-tetrahydro-1H-pyrrolo[3,2-c]quinoline scaffold were designed and synthesized, and their inhibitory activities against Kv2.1 were evaluated. As a result,2,3-dihydro-1H-pyrrolo[3,2-c]quinoline derivatives 3a and 5a were identified as potent inhibitors of Kv2.1 with IC(50) values of 10.2 and 9.0 µmol·L(-1), respectively.
Assuntos
Quinolinas/química , Canais de Potássio Shab/antagonistas & inibidores , Humanos , Relação Estrutura-AtividadeRESUMO
Poly(ADP-ribose)polymerase-1 (PARP-1) has emerged as a promising anticancer drug target due to its key role in the DNA repair process. In this work, a novel series of 1-benzyl-quinazoline-2,4(1H,3H)-dione derivatives were designed and synthesized as human PARP-1 inhibitors, structure-activity relationships were conducted and led to a number of potent PARP-1 inhibitors having IC50 values of single or double digit nanomolar level. Compound 7j was a potent PARP-1 and PARP-2 inhibitor and it could selectively kill the breast cancer cells MX-1 and MDA-MB-468 with mutated BRCA1/2 and PTEN, respectively, in comparison with homologous recombination proficient cell types such as breast cancer cells MDA-MB-231. In addition, compound 7j displayed the strongest potentiation effect on temozolomide in MX-1 cells (PF50=3.77) in this series of PARP-1 inhibitors.
Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases , Quinazolinas/química , Quinazolinas/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Mama/efeitos dos fármacos , Mama/enzimologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/enzimologia , Linhagem Celular Tumoral , Feminino , Humanos , Simulação de Acoplamento Molecular , Poli(ADP-Ribose) Polimerase-1 , Poli(ADP-Ribose) Polimerases/metabolismo , Relação Estrutura-AtividadeRESUMO
Poly(ADP-ribose)polymerase-1 (PARP-1) plays a significant role in the DNA repair process by catalyzing the transfer of ADP-ribose from NAD+ to its receptors. It is a promising anticancer drug target and many PARP-1 inhibitors have been developed and used in the clinical trial. In this work, a series of 3-(2-oxo-2-substituted acetamido)benzamides have been synthesized and their inhibitory activities against PARP-1 were evaluated. Of all the tested compounds, six compounds displayed inhibitory activities with IC50 values ranging from 0.23 to 5.78 µmol.L-1 . The binding pose of compound 5a was predicted using molecular docking to facilitate further structural modification.
Assuntos
Benzamidas/química , Desenho de Fármacos , Inibidores de Poli(ADP-Ribose) Polimerases/síntese química , Antineoplásicos , Reparo do DNA , Humanos , Simulação de Acoplamento Molecular , Inibidores de Poli(ADP-Ribose) Polimerases/química , Poli(ADP-Ribose) PolimerasesRESUMO
A series of novel indole derivatives was synthesized as inhibitors of fructose-1,6-bisphosphatase (FBPase). Extensive structure-activity relationships were conducted and led to a potent FBPase inhibitor 3.9 with an IC50 of 0.99 µM. The binding mode of this series of indoles was predicted using CDOCKER algorithm. The results of this research will shed light on the further design and optimization of novel small molecules as FBPase inhibitors.
Assuntos
Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Frutose-Bifosfatase/antagonistas & inibidores , Indóis/farmacologia , Regulação Alostérica/efeitos dos fármacos , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Frutose-Bifosfatase/metabolismo , Humanos , Indóis/síntese química , Indóis/química , Estrutura Molecular , Proteínas Recombinantes/metabolismo , Relação Estrutura-AtividadeRESUMO
Pin1 is a modular enzyme that accelerates the cis-trans isomerization of phosphorylated-Ser/Thr-Pro (pS/T-P) motifs found in numerous signaling proteins regulating cell growth and neuronal survival. We have used NMR to investigate the interaction of Pin1 with three related ligands that include a pS-P substrate peptide, and two pS-P substrate analogue inhibitors locked in the cis and trans conformations. Specifically, we compared the ligand binding modes and binding-induced changes in Pin1 side-chain flexibility. The cis and trans binding modes differ, and produce different mobility in Pin1. The cis-locked inhibitor and substrate produced a loss of side-chain flexibility along an internal conduit of conserved hydrophobic residues, connecting the domain interface with the isomerase active site. The trans-locked inhibitor produces a weaker conduit response. Thus, the conduit response is stereoselective. We further show interactions between the peptidyl-prolyl isomerase and Trp-Trp (WW) domains amplify the conduit response, and alter binding properties at the remote peptidyl-prolyl isomerase active site. These results suggest that specific input conformations can gate dynamic changes that support intraprotein communication. Such gating may help control the propagation of chemical signals by Pin1, and other modular signaling proteins.
Assuntos
Peptidilprolil Isomerase/química , Peptidilprolil Isomerase/metabolismo , Motivos de Aminoácidos , Ligação Competitiva , Fenômenos Biofísicos , Domínio Catalítico , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Interações Hidrofóbicas e Hidrofílicas , Técnicas In Vitro , Modelos Moleculares , Peptidilprolil Isomerase de Interação com NIMA , Ressonância Magnética Nuclear Biomolecular , Peptidilprolil Isomerase/antagonistas & inibidores , Peptidilprolil Isomerase/genética , Fosforilação , Conformação Proteica , Domínios e Motivos de Interação entre Proteínas , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Eletricidade Estática , Estereoisomerismo , Especificidade por SubstratoRESUMO
Poly(ADP-ribose) polymerase-1 (PARP-1) has emerged as a promising anticancer drug target due to its key role in the DNA repair process. It can polymerize ADP-ribose units on its substrate proteins which are involved in the regulation of DNA repair. In this work, a novel series of para-substituted 1-benzyl-quinazoline-2, 4 (1H, 3H)-diones was designed and synthesized, and the inhibitory activities against PARP-1 of compounds 7a-7e, 8a-8f, 9a-9c and 10a-10c were evaluated. Of all the tested compounds, nine compounds displayed inhibitory activities with IC50 values ranging from 4.6 to 39.2 micromol x L(-1). In order to predict the binding modes of the potent molecules, molecular docking was performed using CDOCKER algorithm, and that will facilitate to further develop more potent PARP-1 inhibitors with a quinazolinedione scaffold.
Assuntos
Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Quinazolinonas/síntese química , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Simulação de Acoplamento Molecular , Estrutura Molecular , Poli(ADP-Ribose) Polimerase-1 , Poli(ADP-Ribose) Polimerases , Quinazolinonas/química , Quinazolinonas/farmacologia , Relação Estrutura-AtividadeRESUMO
Kv2.1 is involved in regulating neuronal excitability and neuronal cell apoptosis, and inhibiting Kv2.1 is a potential strategy to prevent cell death and achieve neuroprotection in ischemic stroke. In this work, a series of novel benzamide derivatives were designed and synthesized as Kv2.1 inhibitors, and extensive structure-activity relationships led to highly potent and selective Kv2.1 inhibitors having IC50 values of 10-8 M. Among them, compound 80 (IC50 = 0.07 µM, selectivity >130 fold over other K+, Na+, and Ca2+ ion channels) was able to decrease the apoptosis of HEK293/Kv2.1 cells induced by H2O2. Furthermore, its anti-ischemic efficacy was demonstrated as it markedly reduced the infarct volume in MCAO rat model. Additionally, compound 80 possessed appropriate plasma PK parameters. It could serve as a probe to investigate Kv2.1 pathological functions and deserved to be further explored.
Assuntos
Fármacos Neuroprotetores , Humanos , Ratos , Animais , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Células HEK293 , Peróxido de Hidrogênio/metabolismo , Canais de Potássio Shab/metabolismo , ApoptoseRESUMO
Inhibiting O-GlcNAcase and thereby up-regulation of the O-GlcNAc levels of tau was a potential approach for discovering AD treatments. Herein, a series of novel highly potent OGA inhibitors embracing a 4-(arylethynyl)piperidine moiety was achieved by capitalizing on the substrate recognition domain. Extensive structure-activity relationships resulted in compound 81 with significant enzymatic inhibition (IC50 = 4.93 ± 2.05 nM) and cellular potency (EC50 = 7.47 ± 3.96 nM in PC12 cells). It markedly increased the protein O-GlcNAcylation levels and reduced the phosphorylation on Ser199, Thr205, and Ser396 of tau in the OA-injured SH-SY5Y cell model, suggesting its potential role for AD treatment. In fact, an in vivo efficacy of ameliorating cognitive impairment was observed following treatment of APP/PS1 mice with compound 81 (100 mg/kg). Additionally, the appropriate plasma PK and beneficial BBB penetration properties were also observed. Compound 81 deserves to be further explored as an anti-AD agent.
Assuntos
Doença de Alzheimer , Inibidores Enzimáticos , Piperidinas , beta-N-Acetil-Hexosaminidases , Doença de Alzheimer/tratamento farmacológico , Animais , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Piperidinas/síntese química , Piperidinas/química , Piperidinas/farmacocinética , Humanos , Relação Estrutura-Atividade , beta-N-Acetil-Hexosaminidases/antagonistas & inibidores , beta-N-Acetil-Hexosaminidases/metabolismo , Ratos , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/uso terapêutico , Inibidores Enzimáticos/farmacocinética , Camundongos , Células PC12 , Descoberta de Drogas , Camundongos Transgênicos , Proteínas tau/metabolismo , Proteínas tau/antagonistas & inibidores , MasculinoRESUMO
This study is to investigate the mechanism and action characteristics of 6-chloro-3-methyl-4-(2-methyoxycarbonylthiophene-3-sulfonyl)-3, 4-dihydroquinoxa-lin-2-(1 H)-one (XU07011) against HIV-1 replication. XU07011 anti-HIV activity was tested by using VSVG/HIV pseudotype viral system and confirmed by HIV-1 live viruses' infectious assay. Time of addition was used to test HIV-1 reverse transcription process. RNA-dependent DNA polymerase activity and RNase H activity were tested by using enzyme linked immunoabsorbent assay and fluorescence method. Wild type and nine NNRTIs-resistant reverse transcriptase enzymatic models and cell-based pharmacological models were used to evaluate XU07011 bio-characteristics. The results showed that XU07011 inhibited HIV-1 replication with IC50 of (0.057 +/- 0.01) micromol x L(-1) which was comparable to nevirapine [IC50: (0.046 +/- 0.01) micromol x L(-1)]. Mechanism study data indicated that XU07011 blocked HIV-1 reverse transcription process through acting on reverse transcriptase RNA-dependent DNA polymerase with IC 50 of (1.1 +/- 0.3) micromol x L(-1). The compound showed no effect on RNase H activity. XU07011 exhibited better activities comparing with nevirapine on K103N mutated NNRTIs-resistant HIV-1 strains. This study could provide a theoretical basis for novel anti-HIV reagents development.
Assuntos
Fármacos Anti-HIV/farmacologia , Quinoxalinas/farmacologia , DNA Polimerase Dirigida por RNA/metabolismo , Tiofenos/farmacologia , Replicação Viral/efeitos dos fármacos , Fármacos Anti-HIV/química , Farmacorresistência Viral , Células HEK293 , HIV-1/fisiologia , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Nevirapina/farmacologia , Ribonuclease H/metabolismoRESUMO
PARP [poly(ADP-ribose)polymerase] represents a novel potential target in cancer therapy. It is involved in a DNA repair process by catalyzing the transfer of ADP-ribose units from NAD to a number of its substrate proteins. In this work, a series of novel azaindole derivatives was designed and synthesized. Moreover, 16 target molecules were screened and 8 compounds displayed inhibitory activity against PARP-1. It has been demonstrated that these azaindoles bearing cycloamine substituents at 2-position were active to both PARP-1 and PARP-2.
Assuntos
Antineoplásicos/síntese química , Compostos Aza/síntese química , Indóis/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Compostos Aza/química , Compostos Aza/farmacologia , Indóis/química , Indóis/farmacologia , Poli(ADP-Ribose) Polimerase-1 , Poli(ADP-Ribose) Polimerases/metabolismoRESUMO
Pin1 (peptidyl-prolyl cis-trans isomerase NIMA-interacting 1) belongs to peptidyl-prolyl cis-trans isomerase (PPIase) and is a novel promising anticancer target. Based on the lead structure of benzophenone, a series of novel diarylether derivatives containing a pyrimidine ring were designed and synthesized. The inhibitory activities on Pin1 of compounds 5a-5d and 6a-6i were evaluated by a protease-coupled enzyme assay. Of all the evaluated compounds, 6 compounds displayed inhibitory activities. Molecular docking was performed using FlexX algorithm to explore the binding mode of the active molecules.
Assuntos
Desenho de Fármacos , Inibidores Enzimáticos/química , Éteres/química , Peptidilprolil Isomerase/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Éteres/síntese química , Éteres/farmacologia , Humanos , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Estrutura Molecular , Peptidilprolil Isomerase de Interação com NIMA , Peptidilprolil Isomerase/metabolismo , Pirimidinas/química , Relação Estrutura-AtividadeRESUMO
Kv2.1 is widely expressed in brain, and inhibiting Kv2.1 is a potential strategy to prevent cell death and achieve neuroprotection in ischemic stroke. Herein, an in silico model of Kv2.1 tetramer structure was constructed by employing the AlphaFold-Multimer deep learning method to facilitate the rational discovery of Kv2.1 inhibitors. GaMD was utilized to create an ion transporting trajectory, which was analyzed with HMM to generate multiple representative receptor conformations. The binding site of RY785 and RY796(S) under the P-loop was defined with Fpocket program together with the competitive binding electrophysiology assay. The docking poses of the two inhibitors were predicted with the aid of the semi-empirical quantum mechanical calculation, and the IGMH results suggested that Met375, Thr376, and Thr377 of the P-helix and Ile405 of the S6 segment made significant contributions to the binding affinity. These results provided insights for rational molecular design to develop novel Kv2.1 inhibitors.
Assuntos
Canais de Potássio Shab , Canais de Potássio Shab/química , Canais de Potássio Shab/metabolismo , Sítios de LigaçãoRESUMO
Both galectin-3 and galectin-8 are involved in cell adhesion, migration, apoptosis, angiogenesis, and inflammatory processes by recognizing galactose-containing glycoproteins. Inhibiting galectin-3/8 activities is a potential treatment for cancer and tissue fibrosis. Herein, a series of novel N-arylsulfonyl-5-aryloxy-indole-2-carboxamide derivatives was disclosed as dual inhibitors toward galectin-3 and galectin-8 C-terminal domain with Kd values of low micromolar level (Cpd53, gal-3: Kd= 4.12 µM, gal-8C: Kd= 6.04 µM; Cpd57, gal-3: Kd= 12.8 µM, gal-8C: Kd= 2.06 µM), which are the most potent and selective noncarbohydrate-based inhibitors toward gal-3/8 isoforms to date. The molecular docking investigations suggested that the unique amino acids Arg144 in galectin-3 and Ser213 in galectin-8C could contribute to their potency and selectivity. The scratch wound assay demonstrated that Cpd53 and Cpd57 were able to inhibit the MRC-5 lung fibroblast cells migration as well. This class of inhibitors could serve as a new starting point for further discovering structurally distinct gal-3 and gal-8C inhibitors to be used in cancer and tissue fibrosis treatment.
RESUMO
PARP-1/2 inhibitors have become an important therapeutic strategy for the treatment of HR-deficient tumors. However, discovery of new inhibitors with an improved and distinct pharmacological file still need enormous explorations. Herein, a series of novel highly potent PARP-1/2 inhibitors bearing an N-substituted piperazinone moiety were achieved. In particular, Cpd36 was identified as a distinct PARP inhibitor, showing remarkable enzymatic activity not only toward PARP-1 (IC50 = 0.94 nM) and PARP-2 (IC50 = 0.87 nM) but also toward PARP-7 (IC50 = 0.21 nM), as well as high selectivity over other PARP isoforms. Furthermore, Cpd36 was orally bioavailable and significantly repressed the tumor growth in both breast cancer and prostate cancer xenograft model. The crystal structures of Cpd36 within PARP-1 and PARP-2 together with the predicted binding mode within PARP-7 revealed its binding features and provided insightful information for further developing highly potent and selective PARP-1 and/or PARP-7 inhibitors.