Serotype-specific differences in the laboratory parameters among hospitalized children with dengue and genetic diversity of dengue viruses circulating in Tamil Nadu, India during 2017.

In 2017, Tamil Nadu, a southern state, had the second highest number of dengue cases from India. In the present study, the serotype-specific differences in the clinical manifestations and laboratory parameters among hospitalized children with dengue were investigated and molecular characterization of the circulating dengue virus (DENV) serotypes during 2017 in Tamil Nadu was performed. Eighty children with dengue-like symptoms consecutively admitted to a tertiary care hospital and positive for DENV NS1 antigen were investigated for DENV serotype utilizing a real-time reverse transcriptase based polymerase chain reaction assay. Complete envelope (E) gene sequencing of the DENV strains was performed. Seventy samples were positive for serotyping (25 DENV-1, 17 DENV-2, six DENV-3, and 22 DENV-4). DENV-4 infections were associated with elevated levels of liver enzymes; Alanine aminotransferase (P = .021) and aspartate aminotransferase (P = .001). However, none of the serotype was associated with any specific clinical features and severe dengue. Asian and American/African genotypes of DENV-1 were cocirculating. The circulating genotype was cosmopolitan for DENV-2 with multiple lineages, genotype III for DENV-3 and genotype I for DENV-4. Unique mutations were present in the 2017 DENV-4 isolates. The present study suggests the association of DENV-4 with elevated liver enzymes in children hospitalized for dengue. Further, the study reports the genetic diversity of DENV circulating in Tamil Nadu during 2017. The study calls for continuous monitoring of the circulating serotypes and genotypes at regional level in India which might result in a region wise database useful in predicting future outbreaks.

Discovery of 2-(1H-indol-5-ylamino)-6-(2,4-difluorophenylsulfonyl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (7ao) as a potent selective inhibitor of Polo like kinase 2 (PLK2).

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.

Eight months of integrated yoga, hydrotherapy and acupuncture on serum IgE levels and symptoms severity of a patient with chronic allergic rhinosinusitis: A case report.

A 27-year-old man with Allergic rhino sinusitis presented to our hospital in July 2020 with complaints of continuous sneezing, coughing while rising from bed for half an hour, and the same complaints repeated in the afternoon for half an hour, as well as a continuous dry cough for half an hour in the evening. He also had complaints of itching and skin rashes, particularly in his limbs. He underwent yoga (45 minutes, 5-6 days a week) including Jalaneti (a yogic cleansing technique, i.e. nasal irrigation with warm salt water for twice a week), hydrotherapy (enema using neem leaves paste mixed with water and steam bath on first day, followed by facial steam on alternate days) and Acupuncture (one session a week) for 8 months. Results showed a reduction in immunoglobulin E (IgE) levels and symptom severity suggesting that integrated yoga, hydrotherapy, and acupuncture are effective in the management of chronic allergic rhinosinusitis. All treatments were well tolerated without adverse effects. Though the result is encouraging, further studies are required with a larger sample size.

Synthesis and biological evaluation of estradiol linked pyrrolo[2,1-c][1,4]benzodiazepine (PBD) conjugates as potential anticancer agents.

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.

Synthesis and biological evaluation of anilino substituted pyrimidine linked pyrrolobenzodiazepines as potential anticancer agents.

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.

Synthesis, anticancer activity and apoptosis inducing ability of anthranilamide-PBD conjugates.

A series of novel anthranilamide linked pyrrolo[2,1-c][1,4]benzodiazepine conjugates were prepared and evaluated for their anticancer activity. The effects of three promising PBD conjugates on cell cycle of cancerous cell line A375 were investigated. These promising compounds showed the characteristic features of apoptosis like enhancement in the levels of p53 and activation of caspase-3.

Synthesis, anticancer activity and mitochondrial mediated apoptosis inducing ability of 2,5-diaryloxadiazole-pyrrolobenzodiazepine conjugates.

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.

Quinazolinone linked pyrrolo[2,1-c][1,4]benzodiazepine (PBD) conjugates: Design, synthesis and biological evaluation as potential anticancer agents.

A series of novel quinazolinone linked pyrrolobenzodiazepine (PBD) conjugates were synthesized. These compounds 4a-f and 5a-f were prepared in good yields by linking C-8 of DC-81 with quinazolinone moiety through different alkane spacers. These conjugates were tested for anticancer activity against 11 human cancer cell lines and found to be very potent anticancer agents with GI(50) values in the range of <0.1-26.2microM. Among all the PBD conjugates, one of the conjugate 5c was tested against a panel of 60 human cancer cells. This compound showed activity for individual cancer cell lines with GI(50) values of <0.1microM. The thermal denaturation studies exhibited effective DNA binding ability compared to DC-81 and these results are further supported by molecular modeling studies. The detailed biological aspects of these conjugates on A375 cell line were studied. It was observed that compounds 4b and 5c induced the release of cytochrome c, activation of caspase-3, cleavage of PARP and subsequent cell death. Further, these compounds when treated with A375 cells showed the characteristic features of apoptosis like enhancement in the levels of p53, p21 and p27 inhibition of cyclin dependent kinase-2 (CDK2) and suppression of NF-kappaB. Moreover, these two compounds 4b and 5c control the cell proliferation by regulating anti-apoptotic genes like (B-cell lymphoma 2) Bcl-2. Therefore, the data generated suggests that these PBD conjugates activate p53 and inhibit NF-kappaB and thereby these compounds could be promising anticancer agents with better therapeutic potential for the suppression of tumours.

Discovery of 8-cyclopentyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carbonitrile (7x) as a potent inhibitor of cyclin-dependent kinase 4 (CDK4) and AMPK-related kinase 5 (ARK5).

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.

Synthesis and biological evaluation of diaryl ether linked DC-81 conjugates as potential antitumor agents.

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.

Design, synthesis, and biological evaluation of (E)-N-aryl-2-arylethenesulfonamide analogues as potent and orally bioavailable microtubule-targeted anticancer agents.

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.

Synthesis and apoptosis inducing ability of new anilino substituted pyrimidine sulfonamides as potential anticancer agents.

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.

Synthesis and biological evaluation of 3,5-diaryl isoxazoline/isoxazole linked 2,3-dihydroquinazolinone hybrids as anticancer agents.

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.

Search for new and novel chemotherapeutics for the treatment of human malignancies.

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.

Synthesis of imidazothiazole-chalcone derivatives as anticancer and apoptosis inducing agents.

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.

Design, synthesis and biological evaluation of 3,5-diaryl-isoxazoline/isoxazole-pyrrolobenzodiazepine conjugates as potential anticancer agents.

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.

Synthesis of pyrrolo[2,1-c][1,4]benzodiazepines and their conjugates by azido reductive cyclization strategy as potential DNA-binding agents.

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.