Evaluation of molecular descriptors for antitumor drugs with respect to noncovalent binding to DNA and antiproliferative activity

Portugal, José

doi:10.1186/1471-2210-9-11

Cited by 18 publications

(9 citation statements)

References 39 publications

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“…DNA-binding molecules or intercalators represent a class of clinically useful drugs [2]. Most of these bind non-covalently to the DNA along the grooves or intercalate at specific sequences [3].…”

Section: Introductionmentioning

confidence: 99%

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

Shahabuddin¹,

Nambiar²,

Advirao³

et al. 2010

Invest New Drugs

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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. Although both MPTQ and morpho-PTQ show similar biophysical properties with high DNA affinity, here we show that they differ in their biological activities. We find that MPTQ is many fold more potent than morpho-PTQ and is cytotoxic against different leukemic cell lines. IC(50) value of methoxy PTQ was estimated between 2-15 µM among the leukemic cells studied, while it was more than 200 µM when morpho-PTQ was used. Cell cycle analysis shows an increase in sub-G1 phase, without any particular cell cycle arrest. Annexin V staining in conjunction with comet assay and DNA fragmentation suggest that MPTQ induces cytotoxicity by activating apoptosis. Thus the observed low IC(50) value of MPTQ makes it a promising cancer chemotherapeutic agent.

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Section: Introductionmentioning

confidence: 99%

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

Shahabuddin¹,

Nambiar²,

Advirao³

et al. 2010

Invest New Drugs

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“…Despite their intricacies, physicochemical properties of probes can be defined numerically through their structural information, so-called descriptors. Descriptors have long been exploited in computational quantitative structure activity relationship study, for instance, to predict aqueous solubility and permeability of drugs 6 7 , binding affinities of antitumor drugs 8 9 and also cellular uptake and localization of fluorescent probes 10 11 .…”

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confidence: 99%

Development of background-free tame fluorescent probes for intracellular live cell imaging

et al. 2016

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Fluorescence labelling of an intracellular biomolecule in native living cells is a powerful strategy to achieve in-depth understanding of the biomolecule's roles and functions. Besides being nontoxic and specific, desirable labelling probes should be highly cell permeable without nonspecific interactions with other cellular components to warrant high signal-to-noise ratio. While it is critical, rational design for such probes is tricky. Here we report the first predictive model for cell permeable background-free probe development through optimized lipophilicity, water solubility and charged van der Waals surface area. The model was developed by utilizing high-throughput screening in combination with cheminformatics. We demonstrate its reliability by developing CO-1 and AzG-1, a cyclooctyne- and azide-containing BODIPY probe, respectively, which specifically label intracellular target organelles and engineered proteins with minimum background. The results provide an efficient strategy for development of background-free probes, referred to as ‘tame' probes, and novel tools for live cell intracellular imaging.

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“…It is well known that most of antitumor drugs are usually used in clinical trials owing to the high correlation between some of binding DNA and their cytoxicity (Portugal 2009). Roughly, 24 antiangiogenic drugs are currently undergoing evaluation in phase I, II, or III clinical trials.…”

Section: Discussionmentioning

confidence: 99%

Antiangiogenetic Effects of 4 Varieties of Grapes In Vitro

Liu¹,

Liu²,

Song³

et al. 2010

Journal of Food Science

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The purpose of this study was to investigate the inhibitory effects of grapes on the human umbilical vein endothelial (HUVE) cells' capillary tube formation and matrix metalloproteinase-2 (MMP-2) expression secreted into the medium. Four different grape varieties (Concord, Niagara, Chardonnay, and Pinot Noir) were extracted using 80% acetone and the extracts were stored at -80 degrees C. The total amount of phenolics and flavonoids for each of the 4 grape varieties were determined by spectrophotometry. Grape extracts were co-cultured with HUVE cells on Matrigel and inhibitory effects on tube formation were observed under a microscope. The inhibitory effects of grape extracts on MMP-2 expression were examined by zymogram. All 4 grape varieties inhibited the tube formation of HUVE cells in a dose-dependent manner on Matrigel. Except for Chardonnay, the other 3 grape varieties completely inhibited secretion of MMP-2 at 20 mg/mL. There was a significant positive relationship between the total phenolics and flavonoids and antiangiogenetic activities. The grapes tested have the potential to inhibit angiogenesis mainly by their phenolics and flavonoids contents, which partly contribute to their cancer chemopreventive efficacy.

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Evaluation of molecular descriptors for antitumor drugs with respect to noncovalent binding to DNA and antiproliferative activity

Cited by 18 publications

References 39 publications

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

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

Development of background-free tame fluorescent probes for intracellular live cell imaging

Antiangiogenetic Effects of 4 Varieties of Grapes In Vitro

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