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1.
Bioorg Med Chem ; 24(4): 521-44, 2016 Feb 15.
Article in English | MEDLINE | ID: mdl-26762835

ABSTRACT

Several families of protein kinases have been shown to play a critical role in the regulation of cell cycle progression, particularly progression through mitosis. These kinase families include the Aurora kinases, the Mps1 gene product and the Polo Like family of protein kinases (PLKs). The PLK family consists of five members and of these, the role of PLK1 in human cancer is well documented. PLK2 (SNK), which is highly homologous to PLK1, has been shown to play a critical role in centriole duplication and is also believed to play a regulatory role in the survival pathway by physically stabilizing the TSC1/2 complex in tumor cells under hypoxic conditions. As a part of our research program, we have developed a library of novel ATP mimetic chemotypes that are cytotoxic against a panel of cancer cell lines. We show that one of these chemotypes, the 6-arylsulfonyl pyridopyrimidinones, induces apoptosis of human tumor cell lines in nanomolar concentrations. The most potent of these compounds, 7ao, was found to be a highly specific inhibitor of PLK2 when profiled against a panel of 288 wild type, 55 mutant and 12 lipid kinases. Here, we describe the synthesis, structure activity relationship, in vitro kinase specificity and biological activity of the lead compound, 7ao.


Subject(s)
Drug Discovery , Indoles/pharmacology , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Pyrimidinones/pharmacology , Dose-Response Relationship, Drug , Humans , Indoles/chemical synthesis , Indoles/chemistry , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Protein Serine-Threonine Kinases/metabolism , Pyrimidinones/chemical synthesis , Pyrimidinones/chemistry , Structure-Activity Relationship
2.
J Med Chem ; 57(3): 578-99, 2014 Feb 13.
Article in English | MEDLINE | ID: mdl-24417566

ABSTRACT

The success of imatinib, a BCR-ABL inhibitor for the treatment of chronic myelogenous leukemia, has created a great impetus for the development of additional kinase inhibitors as therapeutic agents. However, the complexity of cancer has led to recent interest in polypharmacological approaches for developing multikinase inhibitors with low toxicity profiles. With this goal in mind, we analyzed more than 150 novel cyano pyridopyrimidine compounds and identified structure-activity relationship trends that can be exploited in the design of potent kinase inhibitors. One compound, 8-cyclopentyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carbonitrile (7x), was found to be the most active, inducing apoptosis of tumor cells at a concentration of approximately 30-100 nM. In vitro kinase profiling revealed that 7x is a multikinase inhibitor with potent inhibitory activity against the CDK4/CYCLIN D1 and ARK5 kinases. Here, we report the synthesis, structure-activity relationship, kinase inhibitory profile, in vitro cytotoxicity, and in vivo tumor regression studies by this lead compound.


Subject(s)
Antineoplastic Agents/chemical synthesis , Cyclin-Dependent Kinase 4/antagonists & inhibitors , Pyridines/chemical synthesis , Pyrimidines/chemical synthesis , Repressor Proteins/antagonists & inhibitors , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Cell Cycle/drug effects , Cell Line, Tumor , Drug Screening Assays, Antitumor , Female , Heterografts , Humans , Mice , Mice, Nude , Molecular Docking Simulation , Neoplasm Transplantation , Protein Kinases , Pyridines/chemistry , Pyridines/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacology , Structure-Activity Relationship
3.
J Med Chem ; 56(13): 5562-86, 2013 Jul 11.
Article in English | MEDLINE | ID: mdl-23750455

ABSTRACT

A series of novel (E)-N-aryl-2-arylethenesulfonamides (6) were synthesized and evaluated for their anticancer activity. Some of the compounds in this series showed potent cytotoxicity against a wide spectrum of cancer cell-lines (IC50 values ranging from 5 to 10 nM) including all drug resistant cell-lines. Nude mice xenograft assays with compound (E)-N-(3-amino-4-methoxyphenyl)-2-(2',4',6'-trimethoxyphenyl)ethenesulfonamide (6t) showed dramatic reduction in tumor size, indicating their in vivo potential as anticancer agents. A preliminary drug development study with compound 6t is predicted to have increased blood-brain barrier permeability relative to many clinically used antimitotic agents. Mechanistic studies indicate that 6t and some other analogues disrupted microtubule formation, formation of mitotic spindles, and arrest of cells in mitotic phase. Compound 6t inhibited purified tubulin polymerization in vitro and in vivo and circumvented drug resistance mediated by P-glycoprotein. Compound 6t specifically competed with colchicine binding to tubulin and with similar avidity as podophylltoxin, indicating its binding site on tubulin.


Subject(s)
Antineoplastic Agents/pharmacology , Drug Design , Microtubules/drug effects , Neoplasms/drug therapy , Sulfonamides/pharmacology , Xenograft Model Antitumor Assays , Administration, Oral , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacokinetics , Biological Availability , Blood-Brain Barrier/metabolism , Cell Cycle Checkpoints/drug effects , Cell Line, Tumor , Cell Survival/drug effects , Drug Resistance, Neoplasm/drug effects , HCT116 Cells , Humans , K562 Cells , MCF-7 Cells , Mice , Mice, Nude , Microtubules/metabolism , Neoplasms/metabolism , Neoplasms/pathology , Polymerization/drug effects , Sulfonamides/chemical synthesis , Sulfonamides/pharmacokinetics , Tubulin/metabolism , Tumor Burden/drug effects
4.
Anticancer Agents Med Chem ; 13(10): 1590-600, 2013 Dec.
Article in English | MEDLINE | ID: mdl-23438825

ABSTRACT

A series of new diaryl ether linked pyrrolobenzodiazepine (PBD) conjugates (4a-i, 5a-i and 6a-f) was synthesized and evaluated for their anticancer activity against a panel of 11 human cancer cell lines. These conjugates exhibited significant anticancer activity with GI50 values in the range of 0.1-3.88 µM. Some of the potent conjugates (4b, 4h, 5h, 6b, 6c and 6e) were further investigated on cell cycle distribution. FACS analysis showed the accumulation of cells in G0 phase indicating the apoptosis inducing nature of these conjugates. Moreover, compound 6b caused a decrease in the mitochondrial membrane potential, which indicates the apoptotic nature of the compound through mitochondrial mediated pathway. Further conjugates 4b, 4h and 6b induce the activation of caspase and PARP proteins, followed by apoptotic cell death in MCF7 cell line.


Subject(s)
Antineoplastic Agents/pharmacology , Benzodiazepines/pharmacology , Epithelial Cells/drug effects , Gene Expression Regulation, Neoplastic , Mitochondria/drug effects , Pyrroles/pharmacology , Antineoplastic Agents/chemical synthesis , Apoptosis/drug effects , Benzodiazepines/chemical synthesis , Caspase 3/genetics , Caspase 3/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Screening Assays, Antitumor , Epithelial Cells/metabolism , Epithelial Cells/pathology , Ethers , Female , Humans , Inhibitory Concentration 50 , Mammary Glands, Human/drug effects , Mammary Glands, Human/metabolism , Mammary Glands, Human/pathology , Membrane Potential, Mitochondrial/drug effects , Mitochondria/metabolism , Molecular Structure , Poly(ADP-ribose) Polymerases/genetics , Poly(ADP-ribose) Polymerases/metabolism , Pyrroles/chemical synthesis , Resting Phase, Cell Cycle/drug effects , Signal Transduction , Structure-Activity Relationship
5.
Eur J Med Chem ; 46(12): 5817-24, 2011 Dec.
Article in English | MEDLINE | ID: mdl-22000207

ABSTRACT

A series of anilino substituted pyrimidine sulfonamides were prepared and evaluated for their anticancer activity. These sulfonamides showed promising activity with IC(50) values ranging from 5.6 to 12.3 µM. The detailed biological aspects of some of the promising compounds (3d, 3e and 3g) on the K562 cell line were studied. Interestingly, compounds induced G1 cell cycle arrest and down regulation of G1 phase cell cycle regulatory proteins such as cyclin D1, CDK4. These compounds also exhibited inhibition of NF-κB as well as its downstream target gene Akt1 and the phosphorylated form of AKt ser 474 proteins. One of the representative compound 3e could be considered as the potential lead for its development as a new anticancer agent.


Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacology , Sulfonamides/chemistry , Sulfonamides/pharmacology , Apoptosis/drug effects , Cell Line, Tumor , Cyclin D1/metabolism , Down-Regulation/drug effects , G1 Phase/drug effects , Humans , NF-kappa B/genetics , Neoplasms/drug therapy
6.
Bioorg Med Chem ; 19(8): 2565-81, 2011 Apr 15.
Article in English | MEDLINE | ID: mdl-21459581

ABSTRACT

A series of new estradiol linked pyrrolo[2,1-c][1,4]benzodiazepine (E(2)-PBD) conjugates (3a-f, 4a-f and 5a-f) with different linker architectures including a triazole moiety have been designed and synthesized. All the 18 compounds have been evaluated for their anticancer activity and it is observed that some of the compounds particularly 4c-e and 5c,d exhibited significant anticancer activity. The detailed biological aspects relating to the cell cycle effects and tubulin depolymerization activity have been examined with a view to understand the mechanism of action of these conjugates. Among all these conjugates, one of the compound 5c could be considered as the most effective compound particularly against MCF-7 breast cancer cell line.


Subject(s)
Antineoplastic Agents/chemical synthesis , Benzodiazepines/chemical synthesis , Antineoplastic Agents/pharmacology , Benzodiazepines/pharmacology , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Cell Cycle/drug effects , Cell Line, Tumor , Estradiol , Estrogens , Female , Humans , Pyrroles , Structure-Activity Relationship , Tubulin/drug effects
7.
Eur J Med Chem ; 46(2): 691-703, 2011 Feb.
Article in English | MEDLINE | ID: mdl-21194809

ABSTRACT

A series of new 3,5-diaryl isoxazoline/isoxazole linked 2,3-dihydro quinazolinone hybrids with different linker architectures have been designed and synthesized. These compounds have been evaluated for their anticancer activity. One of the compounds 4c amongst this series has shown promising anticancer activity. Further some detailed biological assays relating to the cell cycle aspects and tubulin depolymerization activity have been examined with a view to understand the mechanism of action of this conjugate.


Subject(s)
Antineoplastic Agents/pharmacology , Isoxazoles/pharmacology , Quinazolinones/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Cycle/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Isoxazoles/chemical synthesis , Isoxazoles/chemistry , Molecular Structure , Quinazolinones/chemical synthesis , Quinazolinones/chemistry , Stereoisomerism
8.
ChemMedChem ; 5(11): 1937-47, 2010 Nov 08.
Article in English | MEDLINE | ID: mdl-20836120

ABSTRACT

A new class of imidazo[2,1-b]thiazole chalcone derivatives were synthesized and evaluated for their anticancer activity. These chalcone derivatives show promising activity, with log GI(50) values ranging from -7.51 to -4.00. The detailed biological aspects of these derivatives toward the MCF-7 cell line were studied. Interestingly, these chalcone derivatives induced G(0)/G(1)-phase cell-cycle arrest, down-regulation of G(1)-phase cell-cycle regulatory proteins such as cyclin D1 and cyclin E1, and up-regulation of CDK4. Moreover, these compounds elicit the characteristic features of apoptosis such as enhancement in the levels of p53, p21, and p27, suppression of NF-κB, and up-regulation of caspase-9. One of these chalcone derivatives, 3 d, is potentially well suited for detailed biological studies, either alone or in combination with existing therapies.


Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Cell Cycle/drug effects , Chalcone/chemical synthesis , Chalcone/pharmacology , Antineoplastic Agents/chemistry , Caspase 9/metabolism , Cell Line, Tumor , Chalcone/chemistry , Cyclin-Dependent Kinases/metabolism , Cyclins/metabolism , Female , Humans , Imidazoles/chemical synthesis , Imidazoles/chemistry , Imidazoles/pharmacology , NF-kappa B/metabolism , Thiazoles/chemical synthesis , Thiazoles/chemistry , Thiazoles/pharmacology
9.
Bioorg Med Chem Lett ; 20(17): 5232-6, 2010 Sep 01.
Article in English | MEDLINE | ID: mdl-20673627

ABSTRACT

A series of new anilino substituted pyrimidine linked pyrrolo[2,1-c][1,4]benzodiazepine (PBD) conjugates were prepared and evaluated for their anticancer activity. The effects of four promising PBD conjugates on cell cycle of cancerous cell line A375 were investigated. These compounds showed the characteristic features of apoptosis like enhancement in the levels of p53, release of cytochrome c, and cleavage of PARP.


Subject(s)
Aniline Compounds/chemistry , Benzodiazepines/chemical synthesis , Benzodiazepines/pharmacology , Pyrimidines/chemistry , Benzodiazepines/chemistry , Cell Line, Tumor , Drug Evaluation, Preclinical , Drug Screening Assays, Antitumor , Humans
10.
Bioorg Med Chem ; 18(18): 6666-77, 2010 Sep 15.
Article in English | MEDLINE | ID: mdl-20732817

ABSTRACT

A series of 2,5-diaryloxadiazole linked pyrrolo[2,1-c][1,4]benzodiazepine conjugates have been prepared and evaluated for their anticancer activity. These conjugates have shown promising activity with GI50 values ranging from <0.1 to 0.29 microM. It is observed that some of these conjugates particularly 4a, 4d, 4i and 4l exhibit significant anticancer activity. Some detailed biological assays relating to the cell cycle aspects associated to Bax and caspases have been examined with a view to understand the mechanism of action of these conjugates.


Subject(s)
Antineoplastic Agents/chemical synthesis , Apoptosis , Benzodiazepines/chemistry , Mitochondria/drug effects , Oxadiazoles/chemistry , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , Benzodiazepines/chemical synthesis , Benzodiazepines/therapeutic use , Caspases/metabolism , Cell Cycle/drug effects , Cell Line, Tumor , Cyclin-Dependent Kinase 2/metabolism , Humans , Male , Mice , Mice, Inbred NOD , Neoplasms/drug therapy , Oxadiazoles/chemical synthesis , Tumor Suppressor Protein p53/metabolism , Xenograft Model Antitumor Assays , bcl-2-Associated X Protein/metabolism
11.
Eur J Med Chem ; 45(9): 3924-37, 2010 Sep.
Article in English | MEDLINE | ID: mdl-20557981

ABSTRACT

A series of 3,5-diaryl-isoxazoline/isoxazole linked pyrrolo[2,1-c][1,4]benzodiazepine (PBD) conjugates were prepared. These conjugates showed potent anticancer activity with GI(50) values in the range of <0.1-3.6 microM. Some of these PBD conjugates (6a-c) with promising anticancer activity were further investigated on the cell cycle distribution. Moreover, these PBD conjugates exhibited G0/G1 arrest, enhancement in the levels of p53 protein as well as mitochondrial-mediated intrinsic pathway, leading to release of cytochrome c, activation of caspase-3, cleavage of PARP and subsequent apoptotic cell death. Hence these PBD conjugates with 6a being the most potent one could be be taken up for preclinical studies either alone or in combination with existing therapies.


Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Benzodiazepines/chemistry , Benzodiazepines/pharmacology , Drug Design , Isoxazoles/chemistry , Isoxazoles/pharmacology , Antineoplastic Agents/chemical synthesis , Apoptosis/drug effects , Benzodiazepines/chemical synthesis , Cell Cycle Proteins/metabolism , Cell Line, Tumor/drug effects , Cell Proliferation/drug effects , Gene Expression Regulation, Neoplastic/drug effects , Humans , Inhibitory Concentration 50 , Isoxazoles/chemical synthesis
12.
Mini Rev Med Chem ; 10(5): 405-35, 2010 May.
Article in English | MEDLINE | ID: mdl-20370699

ABSTRACT

One of the hallmarks of cancer is the uncontrolled cell proliferation which causes more deaths among the human diseases throughout the globe. One in eight deaths worldwide are due to cancer, it is the second and third leading cause of death in economically developed and developing countries, respectively. As it is caused by both external and internal factors, a balanced approach to cancer control includes prevention, early detection, and effective treatment. In the treatment of cancer, chemotherapy is one of the practical methods and is widely used employing drugs that can destroy cancer cells by impeding their growth and reproduction. Despite the great strides made in the treatment of cancer over the past 50 years, it continues to be a major health concern and therefore, extensive efforts have been devoted to search for new scaffolds to develop chemotherapeutics. In this perspective, over the past two decades from this laboratory extensive efforts have been made in the development of new chemotherapeutic agents for the treatment of cancer. In this review, glimpses on types of current chemotherapeutic agents based on their action of inhibition and the new molecules that are being developed based on the scaffolds such as pyrrolo[2,1-c][1,4]benzodiazepines, podophyllotoxins, benzothiadiazine 1,1-dioxides, naphthalimides and monastrol across the world as well as in this laboratory have been articulated.


Subject(s)
Antineoplastic Agents/chemistry , Neoplasms/drug therapy , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/therapeutic use , Benzodiazepines/chemical synthesis , Benzodiazepines/chemistry , Benzodiazepines/therapeutic use , Benzothiadiazines/chemical synthesis , Benzothiadiazines/chemistry , Benzothiadiazines/therapeutic use , Humans , Naphthalimides/chemical synthesis , Naphthalimides/chemistry , Naphthalimides/therapeutic use , Podophyllotoxin/chemical synthesis , Podophyllotoxin/chemistry , Podophyllotoxin/therapeutic use , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Pyrimidines/therapeutic use , Thiones/chemical synthesis , Thiones/chemistry , Thiones/therapeutic use
13.
Bioorg Med Chem Lett ; 15(10): 2621-3, 2005 May 16.
Article in English | MEDLINE | ID: mdl-15863329

ABSTRACT

Synthesis of pyrrolo[2,1-c][1,4]benzodiazepines via azido reductive cyclization process employing FeCl3-NaI reagent system. This methodology has been extended for the preparation of new nicotinamido-pyrrolobenzodiazepine hybrids linked through piperazino-alkane-oxy spacers that exhibit good DNA binding affinity.


Subject(s)
Azides/chemistry , Benzodiazepines/chemical synthesis , DNA/metabolism , Benzodiazepines/chemistry , Benzodiazepines/metabolism , Electrophoresis, Agar Gel
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