From Ligand to Complexes:  Inhibition of Human Immunodeficiency Virus Type 1 Integrase by β-Diketo Acid Metal Complexes

Sechi, Mario; Bacchi, Alessia; Carcelli, Mauro; Compari, Carlotta; Duce, Elenia; Fisicaro, E.; Rogolino, Dominga; Gates, Paul J.; Derudas, Marco; Al‐Mawsawi, Laith Q.; Neamati, Nouri

doi:10.1021/jm060193m

Cited by 90 publications

(97 citation statements)

References 66 publications

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“…Since the catalytic center of PA-Nter is considered to be acidic (57), monodeprotonated L-742,001 appears to be the more relevant form. Also, since the diketo acid moiety of L-742,001 is directly connected to position 4 of a piperidine ring, its pK a2 value is expected to be higher than the value of ϳ10 to 11 that we experimentally established for ␣,␥-diketo acid inhibitors of HIV integrase, which instead contain an electron-withdrawing aromatic ring (40). Finally, since the tertiary amine of the piperidine ring could be partially protonated at pH 7.4, we performed an additional docking experiment with the zwitterionic form ( Fig.…”

Section: Docking Of L-742mentioning

confidence: 78%

“…A docking study similar to ours was published before (56), but these researchers considered the dianionic form of L-742,001, whereas we assumed that the DKA was in its monodeprotonated form ( Fig. 1) (40). Since the catalytic center of PA-Nter is considered to be acidic (57), monodeprotonated L-742,001 appears to be the more relevant form.…”

Section: Docking Of L-742mentioning

confidence: 98%

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Mutational Analysis of the Binding Pockets of the Diketo Acid Inhibitor L-742,001 in the Influenza Virus PA Endonuclease

Stevaert

Dallocchio

Dessì

et al. 2013

J Virol

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The influenza virus PA endonuclease, which cleaves capped host pre-mRNAs to initiate synthesis of viral mRNA, is a prime target for antiviral therapy. The diketo acid compound L-742,001 was previously identified as a potent inhibitor of the influenza virus endonuclease reaction, but information on its precise binding mode to PA or potential resistance profile is limited. Computer-assisted docking of L-742,001 into the crystal structure of inhibitor-free N-terminal PA (PA-Nter) indicated a binding orientation distinct from that seen in a recent crystallographic study with L-742,001-bound PA-Nter (R. M. DuBois et al., PLoS Pathog. 8:e1002830, 2012). A comprehensive mutational analysis was performed to determine which amino acid changes within the catalytic center of PA or its surrounding hydrophobic pockets alter the antiviral sensitivity to L-742,001 in cell culture. Marked (up to 20-fold) resistance to L-742,001 was observed for the H41A, I120T, and G81F/V/T mutant forms of PA. Two-to 3-fold resistance was seen for the T20A, L42T, and V122T mutants, and the R124Q and Y130A mutants were 3-fold more sensitive to L-742,001. Several mutations situated at noncatalytic sites in PA had no or only marginal impact on the enzymatic functionality of viral ribonucleoprotein complexes reconstituted in cell culture, consistent with the less conserved nature of these PA residues. Our data provide relevant insights into the binding mode of L-742,001 in the PA endonuclease active site. In addition, we predict some potential resistance sites that should be taken into account during optimization of PA endonuclease inhibitors toward tight binding in any of the hydrophobic pockets surrounding the catalytic center of the enzyme.

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Section: Docking Of L-742mentioning

confidence: 78%

Section: Docking Of L-742mentioning

confidence: 98%

Mutational Analysis of the Binding Pockets of the Diketo Acid Inhibitor L-742,001 in the Influenza Virus PA Endonuclease

Stevaert

Dallocchio

Dessì

et al. 2013

J Virol

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“…Inhibitors 1 and 2 were used as reference compounds. 15 With the exception of 12 and 13, all tested cinnolinone-derivatives, as well as the intermediate 6, did not show any anti-IN activities. Conversely, the 4-amino-derivatives 12 and 13, shared a certain inhibitory activity, thus demonstrating some inhibitory properties of this novel chemical scaffold.…”

Section: Introductionmentioning

confidence: 85%

Investigation of furo[2,3-h]- and pyridazino[3,4-f]cinnolin-3-ol scaffolds as substrates for the development of novel HIV-1 integrase inhibitors

Gomaa¹,

Pala²,

Derudas³

et al. 2011

Arkivoc

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This work is dedicated to Prof. Vito Boido on the occasion of his retirement AbstractWith the aim to develop novel HIV-1 integrase inhibitors, we obtained a set of condensed ring systems based on the furo[2,3-h]cinnolin-3(2H)-one and pyridazino[3,4-f]cinnolin-3-ol scaffolds bearing a potential chelating pharmacophore, which can be involved in the inhibition mechanism of the enzyme. Herein, we report the design, synthesis, structural investigation and preliminary biological results of these heteroaromatic systems.

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“…The required chlorides 6q and 6r were prepared from 13-methyltetradecanoic acid (13-MTA) [14] and 12-methyltetradecanoic acid (12-MTA), respectively. To assess the influence of metal chelation on the bioactivity we also prepared a stable Ca(II) complex of melophlin A, Ca(1a) 2 , by slowly adding an aqueous suspension of CaCO 3 to a methanolic solution of two equivalents of melophlin A and collecting the formed precipitate, similarly to a recently published method [15]. Earlier reports on the effect of metal chelation on the cytotoxic and antimicrobial activity of tetramic acids such as magnesidin [16] [17] and tenuazonic acid [18] were inconclusive.…”

Section: Finally In 2006 Namikoshi Et Al Reported the Extraction Ofmentioning

confidence: 99%

First Syntheses of Melophlins P, Q, and R, and Effects of Melophlins on the Growth of Microorganisms and Tumor Cells

Biersack¹,

Diestel²,

Jagusch³

et al. 2008

Chemistry & Biodiversity

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((Abstract))The marine tetramic acids melophlin P, Q and R were synthesized for the first time in only four steps. Together with the congenerous melophlins A-C, and G they were also tested for antimicrobial and cytotoxic effects. Melophlins B, C, P, Q and R which share a 5-methyl residue showed some antibacterial activity, mainly in Grampositive bacteria. Melophlins B, C and R which have methyl branched 3-acyl side chains in common, inhibited the growth of cells of human KB-3-1 cervix carcinoma, A-498 kidney carcinoma and U-937 leukemia at IC 50 < 10 µM. They were similar in activity to cisplatin. Melophlin Q, also methyl branched, was astoundingly specific in inhibiting A-498 kidney cancer cells while melophlin P inhibited U-937 leukemia cells particularly well. The position of the methyl branch is decisive for the magnitude of the antiproliferative effect of the melophlin couples B/C and R/Q. 3 IntroductionThe melophlins 1 are N-methyl-3-acyltetramic acids that differ only in the substituents at C(5) (H or Me) of the pyrrolidine-2,4-dione core and in the chain length (C 12 to C 16 ) and branching of the 3-acyl residue (Fig. 1) Results and Discussion ChemistryThe melophlins P (1p), Q (1q) and R (1r) were prepared in four steps as previously described for the congeners B and C (Scheme 1) [11]. N-methylalanine t-butyl ester 2 was reacted with 3, the cumulated ylide Ph 3 P=C=C=O, immobilized on polystyrene [12] to give the tetramate 4 in 92% yield as product of a domino addition / intra-Wittig alkenation process. Since the natural products 1p-r had been shown by oxidative degradation to be 1:1 mixtures of (5R)-and (5S)-stereoisomers [3], racemic 2 was employed. Immobilization of the phosphorus ylide greatly facilitated removal of by-product phosphine oxide. Quantitative cleavage of the ester 4 with trifluoroacetic acid (TFA) gave 1,5-dimethylpyrrolidine-2,4-dione 5. This was 3-acylated under Jones' conditions [13] with BF 3 -diethyl etherate and the respective acyl chloride 6, which was racemic in the case of 6r, to furnish the corresponding 5 BF 2 -adducts 7 in a moderate 20-40% yield under classical thermal but in 30-65% yield under microwave irradiation conditions. The BF 2 -chelates 7 were finally converted to melophlins P, Q or R, respectively, by boiling in methanol. The required chlorides 6q and 6r were prepared from 13-methyltetradecanoic acid (13-MTA) [14] and 12-methyltetradecanoic acid (12-MTA), respectively. To assess the influence of metal chelation on the bioactivity we also prepared a stable Ca(II) complex of Biological evaluationKinases and phosphatases play a pivotal role in the signal transduction of cancer cells. As 3-acyltetramates were frequently reported to inhibit these enzymes, we looked for antiproliferative effects of a representative, structurally diverse subset of melophlins (A-C, G, P-R) in human KB-3-1 cervix, human epithelial A-498 kidney carcinoma, and U-937 leukemia cells as well as L929 mouse fibroblasts (Table 1). In terms of stereochemistry, the compounds were prepared and tes...

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From Ligand to Complexes: Inhibition of Human Immunodeficiency Virus Type 1 Integrase by β-Diketo Acid Metal Complexes

Cited by 90 publications

References 66 publications

Mutational Analysis of the Binding Pockets of the Diketo Acid Inhibitor L-742,001 in the Influenza Virus PA Endonuclease

Mutational Analysis of the Binding Pockets of the Diketo Acid Inhibitor L-742,001 in the Influenza Virus PA Endonuclease

Investigation of furo[2,3-h]- and pyridazino[3,4-f]cinnolin-3-ol scaffolds as substrates for the development of novel HIV-1 integrase inhibitors

First Syntheses of Melophlins P, Q, and R, and Effects of Melophlins on the Growth of Microorganisms and Tumor Cells

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