In Vivo Antitumor, Pharmacological and Toxicological Study of Pyrimido[ 4',5':4,5] thieno(2,3-b)quinoline with 9-hydroxy-4-(3-diethylaminopropylamino) and 8-methoxy-4-(3-diethylaminopropylamino) Substitutions.

Background: We previously synthesized two DNA intercalative Pyrimido[4',5':4,5]thieno(2,3-b) quinolines (PTQ), 9-hydroxy-4-(3-diethylaminopropylamino)pyrimido[4',5':4,5]thieno(2,3-b) quinolines (Hydroxy- DPTQ) and 8-methoxy-4-(3-diethylaminopropylamino) pyrimido[4',5':4,5]thieno(2,3-b) quinolines (Methoxy-DPTQ), and reported their cytotoxicity against cancer cell lines.

Methods: In the present study, we sought to analyze the antitumor activity of Hydroxy-DPTQ and Methoxy-DPTQ on Ehrlich's ascites carcinoma in vivo models, along with other pharmacological activities and toxicity.

Results: In this study, both the test molecules studied possess potent in vivo antitumor activity without any hematological, biochemical or nephrotoxicity.

The correlation between insulin and OCT-6 transcription factor in Schwann cells and sciatic nerve of diabetic rats.

Insulin signal is one of the vital signaling cascade required for Schwann cells to myelinate the axons of peripheral nervous system (PNS). Myelin formation of peripheral nerve is a complex molecular event controlled by different neurotrophic and transcription factors. The altered or failure in this signaling progression is one of the reasons behind the demyelination of peripheral neurons in diabetic peripheral neuropathy (DPN).

Insulin-induced upregulation of lipoprotein lipase in Schwann cells during diabetic peripheral neuropathy.

Diabetic peripheral neuropathy (DPN) is one of the major complications associated with diabetes. It is characterized by the degeneration of the myelin sheath around axons, referred to as demyelination. Such demyelinations are often caused by reduced lipid component of the myelin sheath.

Synthesis, DNA binding and cytotoxic activity of pyrimido[4',5':4,5]thieno(2,3-b)quinoline with 9-hydroxy-4-(3-diethylaminopropylamino) and 8-methoxy-4-(3-diethylaminopropylamino) substitutions.

Two new derivatives of pyrimido[4',5';4,5]thieno(2,3-b)quinoline (PTQ), 9-hydroxy-4-(3-diethylaminopropylamino)pyrimido[4',5';4,5]thieno(2,3-b)quinoline (Hydroxy-DPTQ) and 8-methoxy-4-(3-diethylaminopropylamino)pyrimido[4',5';4,5]thieno(2,3-b)quinoline (Methoxy-DPTQ) were synthesized and their DNA binding ability was analyzed using spectroscopy (UV-visible, fluorescence and circular dichroism), ethidium bromide dye displacement assay, melting temperature (T) analysis and computational docking studies. The hypochromism in UV-visible spectrum and increased fluorescence emission of Hydroxy-DPTQ and Methoxy-DPTQ in the presence of DNA suggested the molecule-DNA interaction. The association constants calculated from UV-visible and spectral titrations were of the order 10 to 10M.

Altered expression of IRS2 and GRB2 in demyelination of peripheral neurons: Implications in diabetic neuropathy.

Demyelination of the peripheral nerves and dysfunction of Schwann cells (SCs) are the chronic complications involved in the development of peripheral neuropathy among diabetic patients. Insulin signaling plays an important role in restoring the myelin proteins in diabetic peripheral neuropathy (DPN). Since insulin levels are altered in diabetes, it becomes of great interest to appreciate the role and regulation of docking and adaptor protein, how these proteins respond to variations in the levels of insulin as experienced in juvenile diabetes.

Insulin influenced expression of myelin proteins in diabetic peripheral neuropathy.

Diabetic peripheral neuropathy (DPN) is one of the downstream complications of diabetes. This complication is caused by the deficiency of insulin action and subsequent hyperglycemia, but the details of their pathogenesis remain unclear. Hence, it is of critical importance to understand how such hormonal variation affects the expression of myelin proteins such as myelin basic protein (MBP) and myelin associated glycoprotein (MAG) in the peripheral nerve.

A Novel Anticancer Agent, 8-Methoxypyrimido[4',5':4,5]thieno(2,3-b) Quinoline-4(3H)-One Induces Neuro 2a Neuroblastoma Cell Death through p53-Dependent, Caspase-Dependent and -Independent Apoptotic Pathways.

Neuroblastoma is the most common cancer in infants and fourth most common cancer in children. Despite recent advances in cancer treatments, the prognosis of stage-IV neuroblastoma patients continues to be dismal which warrant new pharmacotherapy. A novel tetracyclic condensed quinoline compound, 8-methoxypyrimido [4',5':4,5]thieno(2,3-b) quinoline-4(3H)-one (MPTQ) is a structural analogue of an anticancer drug ellipticine and has been reported to posses anticancer property.

A novel DNA intercalator, 8-methoxy pyrimido[4',5':4,5]thieno (2,3-b)quinoline-4(3H)-one induces apoptosis in cancer cells, inhibits the tumor progression and enhances lifespan in mice with tumor.

Polycyclic aromatic molecules such as ellipticine intercalate into double-stranded DNA and interfere with physiological functions. In the present study, we evaluate the chemotherapeutic potential of MPTQ on animal models and its mode of action. In order to test the antitumor activity, monohydrochloride of MPTQ was orally administered in mice bearing tumor.

Intercalative pyrimido[4',5':4,5]thieno(2,3-b)quinolines induce apoptosis in leukemic cells: a comparative study of methoxy and morpholino substitution.

DNA intercalating molecules are promising anticancer agents. Polycyclic aromatic molecules such as ellipticine intercalate into double-stranded DNA and affect major physiological functions. In the present study, we have characterized two molecules with the same chemical backbone but different side chains, namely 8-methoxy pyrimido[4',5':4,5]thieno (2,3-b)quinoline-4(3H)-one (MPTQ) and 4-morpholino pyrimido[4',5':4,5]thieno(2,3-b)quinoline (morpho-PTQ) at the 8th and 4th position, respectively.

A novel structural derivative of natural alkaloid ellipticine, MDPSQ, induces necrosis in leukemic cells.

DNA intercalating molecules are promising chemotherapeutic agents. In the present study, a novel DNA intercalating compound of pyrimido[4',5':4,5]selenolo(2,3-b)quinoline series having 8-methyl-4-(3 diethylaminopropylamino) side chain is studied for its chemotherapeutic properties. Our results showed that 8-methyl-4-(3 diethylaminopropylamino) pyrimido [4',5':4,5] selenolo(2,3-b)quinoline (MDPSQ) induces cytotoxicity in a time- and concentration-dependent manner on leukemic cell lines.

A novel DNA intercalator, butylamino-pyrimido[4',5':4,5]selenolo(2,3-b)quinoline, induces cell cycle arrest and apoptosis in leukemic cells.

DNA intercalators are one of the most commonly used chemotherapeutic agents. Novel intercalating compounds of pyrimido[4',5':4,5]selenolo(2,3-b)quinoline series having a butylamino or piperazino group at fourth position (BPSQ and PPSQ, respectively) are studied. Our results showed that BPSQ induced cytotoxicity whereas PPSQ was cytostatic.