Design, synthesis, and evaluation of novel 6-chloro-/fluorochromone derivatives as potential topoisomerase inhibitor anticancer agents.
TL;DR: The compounds displayed promising anticancer activity under these test systems and shall serve as useful 'leads' for further design.
About: This article is published in Bioorganic & Medicinal Chemistry Letters.The article was published on 2006-03-01. It has received 88 citations till now. The article focuses on the topics: Topoisomerase inhibitor & Ehrlich ascites carcinoma.
Citations
More filters
TL;DR: This work was supported by the Foundation for Science and Technology (FCT), Portugal (projects PTDC/QUI-QUI/113687/2009 and PEst-C/QUI/UI0081/2013) and SFRH/BD/61262/2009.
Abstract: This work was supported by the Foundation for Science and Technology (FCT), Portugal (projects PTDC/QUI-QUI/113687/2009 and PEst-C/QUI/UI0081/2013). A.G. (SFRH/BD/43531/2008) and M.J.M. (SFRH/BD/61262/2009) thank FCT for grants.
514 citations
TL;DR: The present review focuses on the pharmacological profile of chromone derivatives in the current literature with an update of recent research findings on this nucleus and the perspectives that they hold for future research.
331 citations
TL;DR: 6/6,7-Substituted-3-formylchromones (8a-g) were reacted with 2 equivalents thiobenzamide in refluxing toluene to furnish substituted-3-(5-phenyl-3H-[1,2,4]dithiazol- 3-yl)chromen-4-ones (10a-G) in high yields.
148 citations
TL;DR: The differential analysis of the solvation effects among the chromone isomers gave additional insight about the superior outline of the 3-substituted chromone derivatives, which act preferably as MAO-B inhibitors.
Abstract: Two series of novel chromone derivatives were synthesized and investigated for their ability to inhibit the activity of monoamine oxidase. The SAR data indicate that chromone derivatives with substituents in position 3 of γ-pyrone nucleus act preferably as MAO-B inhibitors, with IC(50) values in the nanomolar to micromolar range. Almost all chromone 3-carboxamides display selectivity toward MAO-B. Identical substitutions on position 2 of γ-pyrone nucleus result in complete loss of activity in both isoforms (chromones 2-12 except 3 and 5). Notably, chromone (19) exhibits an MAO-B IC(50) of 63 nM, greater than 1000-fold selectivity over MAO-A, and behaves as a quasi-reversible inhibitor. Docking experiments onto the MAO binding of the most active compound highlight different interaction patterns among the isoforms A and B. The differential analysis of the solvation effects among the chromone isomers gave additional insight about the superior outline of the 3-substituted chromone derivatives.
130 citations
TL;DR: A series of new chromone analogues bearing heterocyclic thioether moiety and aurone analogue bearing cyclic tertiary amine moiety were designed and synthesized under microwave irradiation to present many advantages, such as higher yields, shorter reaction time, mild condition, and readily isolation of the products.
91 citations
References
More filters
TL;DR: It is proposed that camptothecin blocks the rejoining step of the breakage-reunion reaction of mammalian DNA topoisomerase I, which results in the accumulation of a cleavable complex which resembles the transient intermediate proposed for eukaryotic DNATopoisomersase I.
2,254 citations
TL;DR: A method to determine the lipid peroxide level in human serum or plasma and its profile of change in several human diseases is described and Intervention of lipid peroxides in the pathogenesis of certain diseases is also mentioned.
1,313 citations
TL;DR: The various structural features of the quinolones which govern antibacterial efficacy and influence the side-effect profile are delineated and summarized at the molecular level and those groups which mutually improve efficacy while reducing side-effects are identified.
Abstract: The fluoroquinolones represent a major class of antibacterials with great therapeutic potential. Over the years, several structure-activity and side-effect relationships have been developed, covering thousands of analogues, in an effort to improve overall antimicrobial efficacy while reducing undesirable side-effects. In this review, the various structural features of the quinolones which govern antibacterial efficacy and influence the side-effect profile are delineated and summarized at the molecular level. Those features which most remarkably enhance antimicrobial effectiveness are: a halogen (F or Cl) at the 8-position which improves oral absorption and activity against anaerobes; an alkylated pyrrolidine or piperazine at C7 which increases serum half-life and potency vs Gram-positive bacteria; and a cyclopropyl group at N1 and an amino substituent at C5, both of which improve overall potency. Some side-effects of the quinolones are class effects, and cannot be modulated by molecular variation. These include gastrointestinal irritation and arthropathy. Several other potential side-effects are directly influenced by structural modification. For example, CNS effects and drug interactions with theophylline and NSAIDs are strongly influenced by the C7 substituent with simple pyrrolidines and piperazines the worst actors. Increasing steric bulk through alkylation ameliorates these effects. Phototoxicity is determined by the nature of the 8-position substituent with halogen causing the greatest photo reaction while hydrogen and methoxy show little light induced toxicity. Genetic toxicity is controlled in additive fashion by the choice of groups at the 1, 7 and 8 positions. From the analysis, those groups which mutually improve efficacy while reducing side-effects are identified. In addition, preclinical models for determining potential side-effects are discussed.
631 citations
TL;DR: Studies of fluoroquinolone-resistant mutants and purified topoisomerases indicate that many quinolones have differing activities against the two targets, and drugs with similar activities against both targets may prove less likely to select de novo resistance.
Abstract: Five bacterial targets have been exploited in the development of antimicrobial drugs: cell wall synthesis, protein synthesis, ribonucleic acid synthesis, deoxyribonucleic acid (DNA) synthesis, and intermediary metabolism. Because resistance to drugs that interact with these targets is widespread, new antimicrobials and an understanding of their mechanisms of action are vital. The fluoroquinolones are the only direct inhibitors of DNA synthesis; by binding to the enzyme-DNA complex, they stabilize DNA strand breaks created by DNA gyrase and topoisomerase IV. Ternary complexes of drug, enzyme, and DNA block progress of the replication fork. Cytotoxicity of fluoroquinolones is likely a 2-step process involving (1) conversion of the topoisomerase-quinolone-DNA complex to an irreversible form and (2) generation of a double-strand break by denaturation of the topoisomerase. The molecular factors necessary for the transition from step 1 to step 2 remain unclear, but downstream pathways for cell death may overlap with those used by other bactericidal antimicrobials. Studies of fluoroquinolone-resistant mutants and purified topoisomerases indicate that many quinolones have differing activities against the two targets. Drugs with similar activities against both targets may prove less likely to select de novo resistance.
428 citations
Book•
01 Jan 1990
TL;DR: In this paper, the soft file of the book is downloaded and the book can be found on-line in this site by visiting the link page to download the book and it will be easy to do so.
Abstract: Only for you today! Discover your favourite dna topology and its biological effects book right here by downloading and getting the soft file of the book. This is not your time to traditionally go to the book stores to buy a book. Here, varieties of book collections are available to download. One of them is this dna topology and its biological effects as your preferred book. Getting this book b on-line in this site can be realized now by visiting the link page to download. It will be easy. Why should be here?
398 citations