RESUMO
Carbonic Anhydrases (CAs) are a large family of zinc metalloenzymes that catalyze the reversible hydration of carbon dioxide involved in several biological processes. They show a wide diversity in tissue distribution and their subcellular localization. Twenty-two novel phthalazine derivatives were designed, synthesized, and evaluated against four human isoforms: hCAâ I, hCAâ II, hCAâ IX, and hCAâ XII. Compounds appeared to be very active mostly against hCAâ IX (7) and hCAâ I (6) isoforms being more potent than reference drug acetazolamide (AAZ). Some compounds appeared to be very selective with a selectivity index up to 13.8. Furthermore, docking was performed for some of these compounds on all isoforms to understand the possible interactions with the active site. Additionally, the most active compounds against hCAâ IX were subjected to cell viability assay. The anticancer activity of the compounds (3 a-d, 5 d, 5 i, and 5 m) was investigated using two human breast cancer cell lines, i. e. MCF-7 and MDA-MB-231 cells, and the normal counterpart, namely MCF10-A cells.
Assuntos
Antineoplásicos , Inibidores da Anidrase Carbônica , Simulação de Acoplamento Molecular , Ftalazinas , Sulfonamidas , Humanos , Inibidores da Anidrase Carbônica/farmacologia , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Ftalazinas/farmacologia , Ftalazinas/síntese química , Ftalazinas/química , Sulfonamidas/química , Sulfonamidas/farmacologia , Sulfonamidas/síntese química , Relação Estrutura-Atividade , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Anidrases Carbônicas/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Estrutura Molecular , Domínio Catalítico , Células MCF-7 , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Proliferação de Células/efeitos dos fármacosRESUMO
Designing selective PARP-1 inhibitors has become a new strategy for anticancer drug development. By sequence comparison of PARP-1 and PARP-2, we identified a possible selective site (S site) consisting of several different amino acid residues of α-5 helix and D-loop. Targeting this S site, 140 compounds were designed, synthesized, and characterized for their anticancer activities and mechanisms. Compound I16 showed the highest PARP-1 enzyme inhibitory activity (IC50 = 12.38 ± 1.33 nM) and optimal selectivity index over PARP-2 (SI = 155.74). Oral administration of I16 (25 mg/kg) showed high inhibition rates of Hela and SK-OV-3 tumor cell xenograft models, both of which were higher than those of the oral positive drug Olaparib (50 mg/kg). In addition, I16 has an excellent safety profile, without significant toxicity at high oral doses. These findings provide a novel design strategy and chemotype for the development of safe, efficient, and highly selective PARP-1 inhibitors.
Assuntos
Antineoplásicos , Desenho de Fármacos , Poli(ADP-Ribose) Polimerase-1 , Inibidores de Poli(ADP-Ribose) Polimerases , Humanos , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/química , Inibidores de Poli(ADP-Ribose) Polimerases/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Animais , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Poli(ADP-Ribose) Polimerase-1/metabolismo , Camundongos , Relação Estrutura-Atividade , Linhagem Celular Tumoral , Camundongos Nus , Feminino , Ensaios Antitumorais Modelo de Xenoenxerto , Células HeLa , Simulação de Acoplamento Molecular , Camundongos Endogâmicos BALB C , Proliferação de Células/efeitos dos fármacos , Ftalazinas/farmacologia , Ftalazinas/química , Ftalazinas/síntese químicaRESUMO
Several attempts for preparation of 4,4'-(2-thioxoimidazolidine-1,3-diyl)bis(butane-1-sulfonic acid) were not successful despite taking 2 mmol of 1,4-butane sultone in reaction with 1 mmol of imidazolidine-2-thione. Instead, 4-(4,5-dihydro-1H-imidazol-2-ylsulfanyl)butyl hydrogen sulfite (DISBHS) was prepared unexpectedly, characterized and used for the synthesis of diverse pyrazolophthalazines from the one-pot three component condensation reaction of phthalhydrazide, malononitrile and aldehydes under mild conditions.
Assuntos
Ftalazinas , Pirazóis , Aldeídos , Ftalazinas/síntese química , Pirazóis/síntese químicaRESUMO
The PRMT5â¢MTA complex has recently emerged as a new synthetically lethal drug target for the treatment of MTAP-deleted cancers. Here, we report the discovery of development candidate MRTX1719. MRTX1719 is a potent and selective binder to the PRMT5â¢MTA complex and selectively inhibits PRMT5 activity in MTAP-deleted cells compared to MTAP-wild-type cells. Daily oral administration of MRTX1719 to tumor xenograft-bearing mice demonstrated dose-dependent inhibition of PRMT5-dependent symmetric dimethylarginine protein modification in MTAP-deleted tumors that correlated with antitumor activity. A 4-(aminomethyl)phthalazin-1(2H)-one hit was identified through a fragment-based screen, followed by X-ray crystallography, to confirm binding to the PRMT5â¢MTA complex. Fragment growth supported by structural insights from X-ray crystallography coupled with optimization of pharmacokinetic properties aided the discovery of development candidate MRTX1719.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Ftalazinas/uso terapêutico , Proteína-Arginina N-Metiltransferases/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Linhagem Celular Tumoral , Desoxiadenosinas/metabolismo , Feminino , Deleção de Genes , Humanos , Camundongos Nus , Ftalazinas/síntese química , Ftalazinas/metabolismo , Ligação Proteica , Proteína-Arginina N-Metiltransferases/metabolismo , Purina-Núcleosídeo Fosforilase/deficiência , Purina-Núcleosídeo Fosforilase/genética , Tionucleosídeos/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
This research presents the design and synthesis of a novel series of phthalazine derivatives as Topo II inhibitors, DNA intercalators, and cytotoxic agents. In vitro testing of the new compounds against HepG-2, MCF-7, and HCT-116 cell lines confirmed their potent cytotoxic activity with low IC50 values. Topo II inhibition and DNA intercalating activities were evaluated for the most cytotoxic members. IC50 values determination demonstrated Topo II inhibitory activities and DNA intercalating affinities of the tested compounds at a micromolar level. Amongst, compound 9d was the most potent member. It inhibited Topo II enzyme at IC50 value of 7.02 ± 0.54 µM with DNA intercalating IC50 of 26.19 ± 1.14 µM. Compound 9d was then subjected to an in vivo antitumor examination. It inhibited tumour proliferation reducing solid tumour volume and mass. Additionally, it restored liver enzymes, proteins, and CBC parameters near-normal, indicating a remarkable amelioration in their functions along with histopathological examinations.
Assuntos
Antineoplásicos/farmacologia , DNA Topoisomerases Tipo II/metabolismo , DNA/química , Desenho de Fármacos , Simulação de Acoplamento Molecular , Ftalazinas/farmacologia , Inibidores da Topoisomerase II/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Ftalazinas/síntese química , Ftalazinas/química , Relação Estrutura-Atividade , Inibidores da Topoisomerase II/síntese química , Inibidores da Topoisomerase II/química , Células Tumorais CultivadasRESUMO
Twenty new N-substituted-4-phenylphthalazin-1-amine derivatives were designed, synthesized, and evaluated for their anticancer activities against HepG2, HCT-116, and MCF-7 cells as VEGFR-2 inhibitors. HCT-116 was the most sensitive cell line to the influence of the new derivatives. In particular, compound 7f was found to be the most potent derivative among all the tested compounds against the three cancer cell lines, with 50% inhibition concentration, IC50 = 3.97, 4.83, and 4.58 µM, respectively, which is more potent than both sorafenib (IC50 = 9.18, 5.47, and 7.26 µM, respectively) and doxorubicin (IC50 = 7.94, 8.07, and 6.75 µM, respectively). Fifteen of the synthesized derivatives were selected to evaluate their inhibitory activities against VEGFR-2. Compound 7f was found to be the most potent derivative that inhibited VEGFR-2 at an IC50 value of 0.08 µM, which is more potent than sorafenib (IC50 = 0.10 µM). Compound 8c inhibited VEGFR-2 at an IC50 value of 0.10 µM, which is equipotent to sorafenib. Moreover, compound 7a showed very good activity with IC50 values of 0.11 µM, which is nearly equipotent to sorafenib. In addition, compounds 7d, 7c, and 7g possessed very good VEGFR-2-inhibitory activity, with IC50 values of 0.14, 0.17, and 0.23 µM, respectively.
Assuntos
Antineoplásicos/farmacologia , Ftalazinas/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Relação Dose-Resposta a Droga , Doxorrubicina/farmacologia , Células HCT116 , Células Hep G2 , Humanos , Concentração Inibidora 50 , Células MCF-7 , Simulação de Acoplamento Molecular , Ftalazinas/síntese química , Ftalazinas/química , Sorafenibe/farmacologia , Relação Estrutura-AtividadeRESUMO
Leishmaniasis and Chagas diseases are two of the most important parasitic diseases in the world. Both belong to the category of Neglected Tropical Diseases, and they cannot be prevented by vaccination. Their treatments are founded in outdated drugs that possess many pernicious side-effects and they're not easy to administer. With the aim of discovering new compounds that could serve as anti-trypanosomal drugs, an antiparasitic study of a synthetic compound family has been conducted. A series of new 1,4-bis(alkylamino)- and 1-alkylamino-4-chloroazine and benzoazine derivatives 1-4 containing imidazole rings have been synthesized and identified. Their structures showed a possible interest based on previous work. Their inâ vitro anti-Leishmania infantum, anti-L.â braziliensis, anti-L.â donovani and anti-T.â cruzi activity were tested, as well as the inhibition of Fe-SOD enzymes. It was found that some of them exhibited quite relevant values indicative of being worthy of future more detailed studies, as most of them showed activity to more than only one parasite species, especially compound 3 c was active for the three studied Leishmania species and also for T.â cruzi, which is a very interesting trait as it covers a wide spectrum.
Assuntos
Imidazóis/farmacologia , Ftalazinas/farmacologia , Piridazinas/farmacologia , Tripanossomicidas/farmacologia , Animais , Chlorocebus aethiops , Imidazóis/síntese química , Imidazóis/toxicidade , Leishmania braziliensis/efeitos dos fármacos , Leishmania donovani/efeitos dos fármacos , Leishmania infantum/efeitos dos fármacos , Testes de Sensibilidade Parasitária , Ftalazinas/síntese química , Ftalazinas/toxicidade , Piridazinas/síntese química , Piridazinas/toxicidade , Tripanossomicidas/síntese química , Tripanossomicidas/toxicidade , Trypanosoma cruzi/efeitos dos fármacos , Células VeroRESUMO
In the designed compounds, a new linker was inserted in the form of fragments with verified VEGFR-2 inhibitory potential, including an α,ß-unsaturated ketonic fragment, pyrazole, and pyrimidine. Also, new distal hydrophobic moieties were attached to these linkers that are expected to increase the hydrophobic interaction with VEGFR-2 and, consequently, the affinity. These structural optimizations have led us to identify the novel dihydropyrazole derivative 6e as a promising hit molecule. All the new derivatives were evaluated to assess their anticancer activity against three human cancer cell lines, including HepG2, HCT-116, and MCF-7. The results of the in vitro anticancer evaluation study revealed the moderate to excellent cytotoxicity of 6c , 6e , 6g , and 7b , with IC50 values in the low micromolar range. The inhibitory activity of VEGFR-2 was investigated for 16 of the designed compounds. The enzyme assay results of the new compounds were compared with those of sorafenib as a reference VEGFR-2 inhibitor. The obtained results demonstrated that our derivatives are potent VEGFR-2 inhibitors. The most potent derivatives 6c , 6e , 6g , and 7b showed IC50 values in the range of 0.11-0.22 µM. Molecular docking and pharmacokinetic studies were also conducted to rationalize the VEGFR-2 inhibitory activity and to evaluate the ability of the most potent derivatives to be developed as good drug candidates.
Assuntos
Antineoplásicos/farmacologia , Ftalazinas/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Células HCT116 , Células Hep G2 , Humanos , Concentração Inibidora 50 , Células MCF-7 , Simulação de Acoplamento Molecular , Ftalazinas/síntese química , Ftalazinas/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Relação Estrutura-AtividadeRESUMO
Poly(ADP-ribose)polymerase (PARP) is a significant therapeutic target for the treatment of numerous human diseases. Olaparib has been approved as a PARP inhibitor. In this paper, a series of new compounds were designed and synthesized with Olaparib as the lead compound. In order to evaluate the inhibitory activities against PARP1 of the synthesized compounds, in vitro PARP1 inhibition assay and intracellular PARylation assay were conducted. The results showed that the inhibitory activities of the derivatives were related to the type of substituent and the length of alkyl chain connecting the aromatic ring. 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT)-based assay also proved that these compounds demonstrating strong inhibition to PARP1 also have high anti-proliferative activities against BRCA2-deficient cell line (Capan-1). Analysis of the entire results suggest that compound 23 with desirable inhibitory efficiency may hold promise for further in vivo exploration of PARP inhibition.
Assuntos
Desenho de Fármacos , Inibidores de Poli(ADP-Ribose) Polimerases/síntese química , Sítios de Ligação , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Simulação de Acoplamento Molecular , Ftalazinas/síntese química , Ftalazinas/química , Ftalazinas/farmacologia , Piperazinas/síntese química , Piperazinas/farmacologia , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Poli(ADP-Ribose) Polimerase-1/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Relação Estrutura-AtividadeRESUMO
Inhibition of PCAF bromodomain has been validated as a promising strategy for the treatment of cancer. In this study, we report the bioisosteric modification of the first reported potent PCAF bromodomain inhibitor, L-45 to its triazoloquinazoline bioisosteres. Accordingly, three new series of triazoloquinazoline derivatives were designed, synthesized, and assessed for their anticancer activity against a panel of four human cancer cells. Three derivatives demonstrated comparable cytotoxic activity with the reference drug doxorubicin. Among them, compound 22 showed the most potent activity with IC50 values of 15.07, 9.86, 5.75, and 10.79 µM against Hep-G2, MCF-7, PC3, and HCT-116 respectively. Also, compound 24 exhibited remarkable cytotoxicity effects against the selected cancer cell lines with IC50 values of 20.49, 12.56, 17.18, and 11.50 µM. Compounds 22 and 25 were the most potent PCAF inhibitors (IC50, 2.88 and 3.19 µM, respectively) compared with bromosporine (IC50, 2.10 µM). Follow up apoptosis induction and cell cycle analysis studies revealed that the bioisostere 22 could induce apoptotic cell death and arrest the cell cycle of PC3 at the G2/M phase. The in silico molecular docking studies were additionally performed to rationalize the PCAF inhibitory effects of new triazoloquinazoline bioisosteres.
Assuntos
Antineoplásicos/farmacologia , Ftalazinas/farmacologia , Quinazolinas/farmacologia , Triazóis/farmacologia , Fatores de Transcrição de p300-CBP/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Ftalazinas/síntese química , Ftalazinas/química , Quinazolinas/síntese química , Quinazolinas/química , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/química , Fatores de Transcrição de p300-CBP/metabolismoRESUMO
Interleukin (IL)-15 is a pleiotropic cytokine structurally close to IL-2 and sharing with the IL-2Rß and γc receptor (R) subunits. IL-15 plays important roles in innate and adaptative immunity, supporting the activation and proliferation of NK, NK-T, and CD8+ T cells. Over-expression of IL-15 has been shown to participate to the development of inflammatory and autoimmune diseases and diverse T cell malignancies. This study is in continuity of our previous work through which a family of small-molecule inhibitors impeding IL-15/IL-2Rß interaction with sub-micromolar activity has been identified using pharmacophore-based virtual screening and hit optimization methods. With the aim to improve the efficacy and selectivity of our lead inhibitor, specific modifications have been introduced on the basis of optimized SAR and modelisation. The new series of compounds generated have been evaluated for their capacity to inhibit the proliferation as well as the down-stream signaling of IL-15-dependent cells and to bind to IL-15.
Assuntos
Interleucina-15/antagonistas & inibidores , Ftalazinas/química , Ftalazinas/farmacologia , Linhagem Celular , Humanos , Ftalazinas/síntese química , Análise Espectral/métodos , Relação Estrutura-AtividadeRESUMO
A series of 4-aminoalkyl-1(2H)-phthalazinone derivatives was designed and synthesized as potential multifunctional agents for Alzheimer's disease (AD) treatment. In vitro biological assay results demonstrated that most synthesized compounds exhibited significant AChE inhibition, moderate to high MAOs inhibitory potencies and good anti-platelet aggregation abilities. Among them, compound 15b exhibited the highest inhibitory potencies towards MAO-B and MAO-A (IC50 = 0.7 µM and 6.4 µM respectively), moderate inhibition towards AChE (IC50 = 8.2 µM), and good activities against self- and Cu2+-induced Aß1-42 aggregation and platelet aggregation. Moreover, 15b also displayed antioxidant capacity, neuroprotective potency, anti-neuroinflammation and BBB permeability. These excellent results indicated that compound 15b could be worthy of further studies to be considered as a promising multifunctional candidate for the treatment of AD.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/farmacologia , Desenho de Fármacos , Inibidores da Monoaminoxidase/farmacologia , Fármacos Neuroprotetores/farmacologia , Ftalazinas/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Animais , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Electrophorus , Humanos , Estrutura Molecular , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/química , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/metabolismo , Ftalazinas/síntese química , Ftalazinas/química , Agregação Plaquetária/efeitos dos fármacos , Agregados Proteicos/efeitos dos fármacos , Ratos , Relação Estrutura-AtividadeRESUMO
New chemotherapeutics are needed to treat hepatocellular carcinoma (HCC), and menaquinones, homologs of vitamin K consisting of a 1,4-naphthoquinone core and a (poly)isoprene chain, are potential candidates. In this study, we designed and synthesized a series of phthalazine-1,4-dione-based menaquinone analogs. Among them, compounds bearing the intact isoprene chain exhibited selective antiproliferative activity towards HCC cell line JHH7, as compared with normal hepatocytes. The geranyl derivative 10 showed submicromolar potency, and might be a promising lead compound for anticancer agents.
Assuntos
Antineoplásicos/farmacologia , Desenho de Fármacos , Ftalazinas/farmacologia , Vitamina K 2/análogos & derivados , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Ftalazinas/síntese química , Ftalazinas/química , Relação Estrutura-Atividade , Vitamina K 2/síntese química , Vitamina K 2/química , Vitamina K 2/farmacologiaRESUMO
In accordance with the significant impetus of the discovery of potent vascular endothelial growth factor receptor 2 (VEGFR-2) inhibitors, herein, we report the design, synthesis, and anticancer evaluation of 12 new N-substituted-4-phenylphthalazin-1-amine derivatives against HepG2, HCT-116, and MCF-7 cells as VEGFR-2 inhibitors. The results of the cytotoxicity investigation indicated that HCT-116 and MCF-7 were the most sensitive cell lines to the influence of the newly synthesized derivatives. In particular, compound 7a was found to be the most potent derivative among all the tested compounds against the three cancer cell lines, HepG2, HCT116, and MCF-7, with IC50 = 13.67 ± 1.2, 5.48 ± 0.4, and 7.34 ± 0.6 µM, respectively, which is nearly equipotent to that of sorafenib (IC50 = 9.18 ± 0.6, 5.47 ± 0.3, and 7.26 ± 0.3 µM, respectively). All synthesized derivatives, 4a,b-8a-c, were evaluated for their inhibitory activities against VEGFR-2. The tested compounds displayed high to low inhibitory activity, with IC50 values ranging from 0.14 ± 0.02 to 9.54 ± 0.85 µM. Among them, compound 7a was found to be the most potent derivative that inhibited VEGFR-2 at an IC50 value of 0.14 ± 0.02 µM, which is nearly 72% of that of the sorafenib IC50 value (0.10 ± 0.02 µM). Compounds 7b, 8c, 8b, and 8a exhibited very good activity with IC50 values of 0.18 ± 0.02, 0.21 ± 0.03, 0.24 ± 0.02, and 0.35 ± 0.04 µM, respectively. Molecular modeling studies were carried out for all compounds against the VEGFR-2 active site. The data obtained from biological testing highly correlated with that obtained from molecular modeling studies. However, these modifications led to new phthalazine derivatives with higher VEGFR-2 inhibitory activities than vatalanib and which are nearly equipotent to sorafenib.
Assuntos
Aminas/farmacologia , Antineoplásicos/farmacologia , Ftalazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Aminas/síntese química , Aminas/química , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Ftalazinas/síntese química , Ftalazinas/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
In an attempt to find new potent cytotoxic compounds, several mono- and bis-pyrazolophthalazines 4a-m and 6a-h were synthesized through an efficient, one-pot, three- and pseudo five-component synthetic approach. All derivatives were evaluated for their in vitro cytotoxic activities against four human cancer cell lines of A549, HepG2, MCF-7, and HT29. Compound 4e showed low toxicity against normal cell lines (MRC-5 and MCF 10A, IC50 > 200 µM) and excellent cytotoxic activity against A549 cell line with IC50 value of 1.25 ± 0.19 µM, which was 1.8 times more potent than doxorubicin (IC50 = 2.31 ± 0.13 µM). In addition, compound 6c exhibited remarkable cytotoxic activity against A549 and MCF-7 cell lines (IC50 = 1.35 ± 0.12 and 0.49 ± 0.01 µM, respectively), more than two-fold higher than that of doxorubicin. The binding properties of the best active mono- and bis-pyrazolophthalazine (4e and 6c) with HSA and DNA were fully evaluated by various techniques including UV-Vis absorption, circular dichroism (CD), Zeta potential and dynamic light scattering analyses indicating interaction of the compounds with the secondary structure of HSA and significant change of DNA conformation, presumably via a groove binding mechanism. Additionally, molecular docking and site-selective binding studies confirmed the fundamental interaction of compounds 4e and 6c with base pairs of DNA. Compounds 4e and 6c showed promising features to be considered as potential lead structures for further studies in cancer therapy.
Assuntos
Antineoplásicos/farmacologia , DNA/química , Desenho de Fármacos , Simulação de Acoplamento Molecular , Ftalazinas/farmacologia , Albumina Sérica Humana/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Sítios de Ligação/efeitos dos fármacos , Bovinos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Ftalazinas/síntese química , Ftalazinas/química , Relação Estrutura-AtividadeRESUMO
Fused diaza-heterocycles constitute the core structure of numerous bioactive natural products and effective therapeutic drugs. Among them, phthalazines have been recognized as remarkable structural leads in medicinal chemistry due to their wide application in pharmaceutical and agrochemical industries. Accessing such challenging pharmaceutical agents/drug candidates with high chemical complexity through synthetically efficient approaches remains an attractive goal in the contemporary medicinal chemistry and drug discovery arena. In this review, we focus on the recent developments in the synthetic routes towards the generation of phthalazine-based active pharmaceutical ingredients and their biological potential against various targets. The general reaction scope of these innovative and easily accessible strategies was emphasized focusing on the functional group tolerance, substrate and coupling partner compatibility/limitation, the choice of catalyst, and product diversification. These processes were also accompanied by the mechanistic insights where deemed appropriate to demonstrate meaningful information. Moreover, the rapid examination of the structure-activity relationship analyses around the phthalazine core enabled by the pharmacophore replacement/integration revealed the generation of robust, efficient, and more selective compounds with pronounced biological effects. A large variety of in silico methods and ADME profiling tools were also employed to provide a global appraisal of the pharmacokinetics profile of diaza-heterocycles. Thus, the discovery of new structural leads offers the promise of improving treatments for various tropical diseases such as tuberculosis, leishmaniasis, malaria, Chagas disease, among many others including various cancers, atherosclerosis, HIV, inflammatory, and cardiovascular diseases. We hope this review would serve as an informative collection of structurally diverse molecules enabling the generation of mature, high-quality, and innovative routes to support the drug discovery endeavors.
Assuntos
Desenvolvimento de Medicamentos , Ftalazinas/farmacologia , Química Farmacêutica , Doença , Humanos , Estrutura Molecular , Ftalazinas/síntese química , Ftalazinas/químicaRESUMO
G-protein coupled receptor kinase 2 (GRK2), which is upregulated in the failing heart, appears to play a critical role in heart failure (HF) progression in part because enhanced GRK2 activity promotes dysfunction of ß-adrenergic signaling and myocyte death. An orally bioavailable GRK2 inhibitor could offer unique therapeutic outcomes that cannot be attained by current heart failure treatments that directly target GPCRs or angiotensin-converting enzyme. Herein, we describe the discovery of a potent, selective, and orally bioavailable GRK2 inhibitor, 8h, through high-throughput screening, hit-to-lead optimization, structure-based design, molecular modelling, synthesis, and biological evaluation. In the cellular target engagement assays, 8h enhances isoproterenol-mediated cyclic adenosine 3',5'-monophosphate (cAMP) production in HEK293 cells overexpressing GRK2. Compound 8h was further evaluated in a human stem cell-derived cardiomyocyte (HSC-CM) contractility assay and potentiated isoproterenol-induced beating rate in HSC-CMs.
Assuntos
Quinase 2 de Receptor Acoplado a Proteína G/antagonistas & inibidores , Ftalazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/farmacologia , Animais , Ensaios Enzimáticos , Quinase 2 de Receptor Acoplado a Proteína G/metabolismo , Células HEK293 , Humanos , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Estrutura Molecular , Miócitos Cardíacos/efeitos dos fármacos , Ftalazinas/síntese química , Ftalazinas/farmacocinética , Ligação Proteica , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacocinética , Quinazolinas/síntese química , Quinazolinas/metabolismo , Quinazolinas/farmacocinética , Relação Estrutura-AtividadeRESUMO
A series of novel 4-substituted phthalazinones as Aurora B kinase inhibitors was synthesized and evaluated the anti-proliferative activities against A549, HCT116, MCF-7 and HepG2 cells. 1-(4-(2-((4-Oxo-3,4-dihydrophthalazin-1-yl)amino)ethyl) phenyl)-3-(3-(trifluoromethyl)phenyl)urea (17b) exhibited the most potent anti-proliferative activity against HCT116 cells with IC50 value of 4.35 ± 1.21 µM, as well as the moderate Aurora B inhibitory activity with the IC50 value of 142 nM. Furthermore, 17b inhibited the phosphorylation of Aurora B on Thr232, leading to cell cycle arrest in the G2/M phase by down-regulating the expression of CyclinB1 and Cdc2 proteins, and apoptosis by up-regulating the expression of BAD and Bax proteins in HCT116 cells. In addition, a docking study revealed that 17b could form key hydrogen bonds with Ala173, Glu171 and Glu177 in Aurora B. All the results reveal that 17b is worthy of further development as an Aurora B kinase inhibitor.
Assuntos
Antineoplásicos/farmacologia , Aurora Quinase B/antagonistas & inibidores , Ftalazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Apoptose/efeitos dos fármacos , Aurora Quinase B/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Ensaios Enzimáticos , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Fosforilação/efeitos dos fármacos , Ftalazinas/síntese química , Ftalazinas/metabolismo , Ligação Proteica , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/metabolismo , Relação Estrutura-AtividadeRESUMO
Herein we report the design and synthesis of a new series of phthalazine derivatives as Topo II inhibitors and DNA intercalators. The synthesized compounds were in vitro evaluated for their cytotoxic activities against HepG-2, MCF-7 and HCT-116 cell lines. Additionally, Topo II inhibitory activity and DNA intercalating affinity were investigated for the most active compounds as a potential mechanism for the anticancer activity. Compounds 15h, 23c, 32a, 32b, and 33 exhibited the highest activities against Topo II with IC50 ranging from 5.44 to 8.90 µM, while compounds 27 and 32a were found to be the most potent DNA binders at IC50 values of 36.02 and 48.30 µM, respectively. Moreover, compound 32a induced apoptosis in HepG-2 cells and arrested the cell cycle at the G2/M phase. Besides, compound 32a showed Topo II poisoning effect at concentrations of 2.5 and 5 µM, and Topo II catalytic inhibitory effect at a concentration of10 µM. In addition, compound 32b showed in vivo a significant tumor growth inhibition effect. Furthermore, molecular docking studies were carried out against DNA-Topo II complex and DNA to investigate the binding patterns of the designed compounds.
Assuntos
Antineoplásicos/uso terapêutico , Substâncias Intercalantes/uso terapêutico , Neoplasias/tratamento farmacológico , Ftalazinas/uso terapêutico , Inibidores da Topoisomerase II/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , DNA/metabolismo , DNA Topoisomerases Tipo II/metabolismo , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Substâncias Intercalantes/síntese química , Substâncias Intercalantes/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Ftalazinas/síntese química , Ftalazinas/metabolismo , Ligação Proteica , Ratos , Relação Estrutura-Atividade , Inibidores da Topoisomerase II/síntese química , Inibidores da Topoisomerase II/metabolismoRESUMO
Phthalazinones are important nitrogen-rich heterocyclic compounds which have been a topic of considerable medicinal interest because of their diversified pharmacological activities. This versatile scaffold forms a common structural feature for many bioactive compounds, which leads to the design and development of novel anticancer drugs with fruitful results. The current review article discusses the progressive development of novel phthalazinone analogues that are targets for various receptors such as PARP, EGFR, VEGFR-2, Aurora kinase, Proteasome, Hedgehog pathway, DNA topoisomerase and P-glycoprotein. It describes mechanistic insights into the anticancer properties of phthalazinone derivatives and also highlights various simple and economical techniques for the synthesis of phthalazinones.