Subrata Sen

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.

Effect of Azadirachta indica on paracetamol-induced hepatic damage in albino rats.

Azadirachta indica, a plant used widely in Ayurveda, has been reported to have anti-inflammatory, immunomodulatory and adaptogenic properties. The present study evaluates its hepatoprotective role. Fresh juice of tender leaves of Azadirachta indica (200 mg/kg body wt. p.o.) inhibited paracetamol (2 g/kg body wt. p.o.)-induced lipid peroxidation and prevented depletion of sulfhydryl groups in liver cells. There was an increase in serum marker enzymes of hepatic damage (aspartate transaminase, alanine transaminase and alkaline phosphatase) after paracetamol administration. Azadirachta indica pretreatment stabilized the serum levels of these enzymes. Histopathological observations of liver tissues corroborated these findings.

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, DNA-binding ability and evaluation of antitumour activity of triazolo[1,2,4]benzothiadiazine linked pyrrolo[2,1-c][1,4]benzodiazepine conjugates.

A series of triazolobenzothiadiazine-pyrrolobenzodiazepine conjugates linked through different alkane spacers have been prepared. These compounds have exhibited significant cytotoxicity against most of the cell lines examined. Compound 5a displays GI(50) values from 1.83 to 2.38 microM against seven human tumour cell lines, and is identified as a promising lead compound from this series. Their DNA thermal denaturation studies have also been carried out, and one of the compounds 5c elevates the DNA helix melting temperature of the CT-DNA by 2.6 degrees C after incubation for 36 h.

Phosphonate-linked pyrrolo[2,1-c][1,4]benzodiazepine conjugates: synthesis, DNA-binding affinity and cytotoxicity.

Pyrrolobenzodiazepine-diethylphosphonate conjugates have been designed and synthesized that link through two different types of spacers that are simple alkane chain and also a piperazine moiety side-armed with the alkane chains. These pyrrolobenzodiazepine conjugates have exhibited remarkable DNA-binding affinity and improved solubility in water, a representative compound 7d showing promising in vitro cytotoxicity.

Synthesis of Aryl‐Substituted Naphthalene‐Linked Pyrrolobenzodiazepine Conjugates as Potential Anticancer Agents with Apoptosis‐Inducing Ability

A library of new aryl‐substituted naphthalene C8‐linked pyrrolo[2,1‐c][1,4]benzodiazepine (PBD) conjugates with various linker architectures were designed, synthesized, and evaluated for their anticancer activity against a panel of 11 human cancer cell lines. All 32 conjugates show anticancer potential, with some of them exhibiting particularly high activity (0.01–0.19 μM). Thermal denaturation studies showed effective DNA binding capacity relative to DC‐81. In assays for biological activity relating to cell‐cycle distribution, these PBD conjugates induce G0/G1‐phase arrest and also cause an increase in the levels of p53 and caspase‐9 proteins, followed by apoptotic cell death. One conjugate in particular is the most promising candidate of the series, with the potential to be selected for further studies, either alone or in combination with existing anticancer therapies.

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.

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.

Aspergillus fumigatus Specific Antibodies in Multitransfused Children with Human Immunodeficiency Virus (HIV) Infection in Relation to Serum Levels of Interleukin-2, Gamma Interferon and Tumour Necrosis Factor

Anti-Aspergillus fumigatus antibodies (IgG and IgE class) and serum levels of cytokines (gamma Interferon, Interleukin-2 and tumour necrosis factor-alpha) were studied in multitransfused (MT) children in relation to human immunodeficiency virus (HIV) infection. The specific antibodies to Aspergillus fumigatus were present in 25 per cent of MT children seropositive for HIV as compared to only 2 per cent among HIV-negative MT children (X2 = 14, P < 0.001). Estimation of serum cytokines level in MT children showed that the asymptomatic HIV-infected children had elevated levels of gamma interferon (Y-IFN) and tumor necrosis factor-alpha (TNF-alpha) without any alteration of Interleukin-2 (IL-2) level, compared to HIV-negative group. However, clinically diagnosed cases of AIDS in the HIV-infected group showed elevation of all the three cytokines levels as compared to HIV negative group, as well as asymptomatic HIV infected group. Presence or absence of concomitant A. fumigatus infection did not lead to alteration of Y-IFN and IL-2 level in the HIV infected group, while TNF-alpha levels were markedly raised in the cases with evidences of presence of A. fumigatus specific antibodies irrespective of whether the group belonged to asymptomatic HIV infection or clinically proven cases of AIDS. The significance of these altered cytokines profile with respect to occurence of A. fumigatus infection in HIV-positive MT children has been discussed.