Epoxide-containing side chains enhance antiproliferative activity of paullones

Xie, Xu; Lemcke, Thomas; Gussio, Rick; Zaharevitz, Daniel; Leost, Maryse; Meijer, Laurent; Kunick, Conrad

doi:10.1016/j.ejmech.2005.02.004

Cited by 40 publications

(8 citation statements)

References 24 publications

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“…All complexes show remarkably high antiproliferative activities in human cancer cell lines with IC 50 values in the 10 -7 to 10 -5 M concentration range, depending on the cell line. Like in the case of paullones, the electronic properties of substituents in position 2 have no distinct effect on cytotoxicity, 45,46 although electron-withdrawing substituents tend to be disadvantageous for cytotoxic activity, whereas an electron-donating methyl group is not. The formylpyridine series was at least as active as the acetylpyridine analogues.…”

Section: Resultsmentioning

confidence: 99%

Ruthenium− and Osmium−Arene Complexes of 2-Substituted Indolo[3,2-c]quinolines: Synthesis, Structure, Spectroscopic Properties, and Antiproliferative Activity

et al. 2010

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The synthesis of new modified indolo[3,2-c]quinoline ligands L1−L8 with metal-binding sites is reported. By coordination to ruthenium− and osmium−arene moieties 16 complexes of the type [(η6-p-cymene)M(L)Cl]Cl (1a,b−8a,b), where M is RuII or OsII and L is L1−L8, have been prepared. All compounds were comprehensively characterized by elemental analysis, electrospray ionization mass spectrometry, IR, UV−vis, and NMR spectroscopy, thermogravimetric analysis, and single-crystal X-ray diffraction (2a, 4a, 4b, 5a, 7a, and 7b). The complexes were tested for antiproliferative activity in vitro in three human cancer cell lines, namely, CH1 (ovarian carcinoma), SW480 (colon adenocarcinoma), and A549 (non-small-cell lung cancer), yielding IC50 values in the submicromolar or low micromolar range.

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Section: Resultsmentioning

confidence: 99%

Ruthenium− and Osmium−Arene Complexes of 2-Substituted Indolo[3,2-c]quinolines: Synthesis, Structure, Spectroscopic Properties, and Antiproliferative Activity

et al. 2010

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“…25,26 Another strategy for minimizing drug resistance is to develop irreversible rather than reversible inhibitors of HIV-1 PR. [27][28][29][30][31][32][33][34][35][36][37] Irreversible inhibitors are less sensitive to mutations because even a low degree of active-site occupancy can lead in time to complete inactivation of the protein. The catalytic aspartate residues are the ideal target for such irreversible inhibitors, because their mutation results in the complete loss of catalytic activity.…”

Section: Introductionmentioning

confidence: 99%

Theoretical study on the mechanism of a ring-opening reaction of oxirane by the active-site aspartic dyad of HIV-1 protease

Kóňa¹

2008

Org. Biomol. Chem.

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Two possible mechanisms of the irreversible inhibition of HIV-1 protease by epoxide inhibitors are investigated on an enzymatic model using ab initio (MP2) and density functional theory (DFT) methods (B3LYP, MPW1K and M05-2X). The calculations predict the inhibition as a general acid-catalyzed nucleophilic substitution reaction proceeding by a concerted SN2 mechanism with a reaction barrier of ca. 15-21 kcal mol(-1). The irreversible nature of the inhibition is characterized by a large negative reaction energy of ca. -17-(-24) kcal mol(-1). A mechanism with a direct proton transfer from an aspartic acid residue of the active site onto the epoxide ring has been shown to be preferred compared to one with the proton transfer from the acid catalyst facilitated by a bridging catalytic water molecule. Based on the geometry of the transition state, structural data important for the design of irreversible epoxide inhibitors of HIV-1 protease were defined. Here we also briefly discuss differences between the epoxide ring-opening reaction in HIV-1 protease and epoxide hydrolase, and the accuracy of the DFT method used.

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“…16 It is evident from the literature that heterocyclics that contain quinolones, 17 carbazoles, 18 azepinones 19 etc. in their molecules exhibit a wide variety of biological activities such as, anti-mycobacterial, 20 anti-leishmanicidal, 21 antitumor, 22 anti-proliferative 23 and anti-leukemic 24 etc. With a view to explore their pharmaceutical potential further, it occurred to as mind to undertake the synthesis of some such molecules which incorporated (a) quinoline-4-carboxylic acid and azepinone framework (b) diazocene pharmacophores on to the carbazole nucleus.…”

Section: Introductionmentioning

confidence: 99%

An Expeditious Approach to the Synthesis of Novel Quinolino and Diazacino Condensed Analogues of Azepino [3, 2-b] Carbazole-2-one of Medicinal Interest

Agrawal¹,

Dwivedi²,

Kishore³

et al. 2022

IJPER

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Background: Quinolino and diazacino are important heterocyclics moiety, which have been reported to possess various activities such as antiallergenic, antifungal, hypocholesterolemic, antibacterial and antiviral activities. The activities of these compounds were related to inhibition of bacterial dehydrogenase enzyme which is one of the important targets studied for designing of antimicrobial drugs. Further, molecular docking approached is used in the present study for confirming potent molecules. Objectives: Aim of the study is to synthesize a series of quinolino and diazacino condensed analogues and evaluation of their anti-microbial activity. Methods: Quinolino and diazacino condensed analogues of azepino [3, 2-b] carbazole-2-one were synthesized by Friedel-Craft acylation and Pfitzinger reaction. Structures of synthesized compounds were characterized by FTIR and HNMR and were evaluated for antimicrobial activity by in-vitro bacterial dehydrogenase activity agar well diffusion assay. Further, in order to determine the binding affinity, molecular docking of synthesized compounds was also performed using bacterial (3NUH of E. coli) and fungal proteins (1FI4). In addition, bacterial dehydrogenase inhibitory activity of most active compound was performed using MTT assay. Results: Synthesized compounds (3, 4 and 6) caused impressive antibacterial and antifungal activities in-vitro assay when compared to the ciprofloxacin and fluconazole. And molecular docking studies also revealed that the synthesized compounds 3, 4 and 6 exhibits good to excellent affinity towards target microbial proteins. Conclusion: Synthesized compounds (3, 4 and 6) hold substantial antibacterial potential and require further exploration to establish them as therapeutic candidates in clinical management.

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Epoxide-containing side chains enhance antiproliferative activity of paullones

Cited by 40 publications

References 24 publications

Ruthenium− and Osmium−Arene Complexes of 2-Substituted Indolo[3,2-c]quinolines: Synthesis, Structure, Spectroscopic Properties, and Antiproliferative Activity

Ruthenium− and Osmium−Arene Complexes of 2-Substituted Indolo[3,2-c]quinolines: Synthesis, Structure, Spectroscopic Properties, and Antiproliferative Activity

Theoretical study on the mechanism of a ring-opening reaction of oxirane by the active-site aspartic dyad of HIV-1 protease

An Expeditious Approach to the Synthesis of Novel Quinolino and Diazacino Condensed Analogues of Azepino [3, 2-b] Carbazole-2-one of Medicinal Interest

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