A New Class of HIV-1 Integrase Inhibitors:  The 3,3,3‘,3‘-Tetramethyl-1,1‘-spirobi(indan)-5,5‘,6,6‘-tetrol Family

Molteni, Valentina; Rhodes, Denise; Rubins, Kathleen H.; Hansen, Mark; Bushman, Frederic D.; Siegel, Jay S.

doi:10.1021/jm990600c

Cited by 56 publications

(25 citation statements)

References 102 publications

(259 reference statements)

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“…Keywords: alkynes · domino reactions · furans · gold · phenols ture which is found in various natural products as well as in pharmacologically active substances. Examples (Scheme 3) are the phenolic sesquiterpene (+)-mutisianthol (10) and related indanes that show antitumor activity; [7] w-(4-aryl-1-piperazinyl)alkoxyindan 11, which possesses antianxiety activity; [8] a whole series of spiro-biindan derivatives 12 that are HIV-1 integrase inhibitors; [9] or the recently isolated trigoxyphin G (13). [10] Classical routes to these targets are based on Friedel-Crafts chemistry like the Haworth naphthalene synthesis.…”

Section: Introductionmentioning

confidence: 99%

Gold Catalysis: Domino Reaction of En‐Diynes to Highly Substituted Phenols

Hashmi

Häffner

Rudolph

et al. 2011

Chemistry A European J

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By Sonogashira coupling of 1,7-heptadiynes and 1,8-octadiynes with 2-iodoallyl alcohols, various substrates that bear a 2-alkynylallyl alcohol moiety tethered to an additional alkyne were prepared in one step. Subjection to nitrogen acyclic carbene (NAC)/gold(I) catalysts delivered highly substituted phenols in an efficient domino reaction. Furan derivatives were formed as intermediates; this was proven by in situ NMR spectroscopy. The uncommon substitution pattern of these furans opens the way for a selective formation of phenols that contain the hydroxyl group in the meta position to the ring junction, which previously was not possible by gold-catalyzed furan-yne cyclization. Furthermore, interesting mechanistic insights were obtained by products derived from secondary allyl alcohols. In this case, in addition to the phenolic compounds, a ketone is formed by 1,2-alkyl shift.

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Section: Introductionmentioning

confidence: 99%

Gold Catalysis: Domino Reaction of En‐Diynes to Highly Substituted Phenols

Hashmi

Häffner

Rudolph

et al. 2011

Chemistry A European J

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“…Indeed, IN from detergent-containing preparations displays more Mn 2+ -dependant than Mg 2+ -dependant activity as compared to detergent-free preparations that quantitatively display similar activities. The difference between cofactors has pharmacological implications, as the apparent efficacy of various IN inhibitors differs between tests using Mg 2+ or Mn 2+ as a cofactor [ 70 - 72 ], and the effects of mutations conferring drug resistance are often detectable only in tests using Mg 2+ as the cofactor [ 73 ]. These considerations have led to the use of chemical groups chelating Mg 2+ in the rational design of integrase inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Integrase and integration: biochemical activities of HIV-1 integrase

et al. 2008

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Integration of retroviral DNA is an obligatory step of retrovirus replication because proviral DNA is the template for productive infection. Integrase, a retroviral enzyme, catalyses integration. The process of integration can be divided into two sequential reactions. The first one, named 3'-processing, corresponds to a specific endonucleolytic reaction which prepares the viral DNA extremities to be competent for the subsequent covalent insertion, named strand transfer, into the host cell genome by a trans-esterification reaction. Recently, a novel specific activity of the full length integrase was reported, in vitro, by our group for two retroviral integrases (HIV-1 and PFV-1). This activity of internal cleavage occurs at a specific palindromic sequence mimicking the LTR-LTR junction described into the 2-LTR circles which are peculiar viral DNA forms found during viral infection. Moreover, recent studies demonstrated the existence of a weak palindromic consensus found at the integration sites. Taken together, these data underline the propensity of retroviral integrases for binding symmetrical sequences and give perspectives for targeting specific sequences used for gene therapy.

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“…The transfer pattern on the target DNA also depends on the nature of the cation (7). Consequently, the efficiency of inhibitors can be different by using either Mg 2ϩ or Mn 2ϩ in assays (8). In each case, the Mg 2ϩ -dependent activity may be more reliable because it is more physiologically relevant.…”

mentioning

confidence: 99%

DNA binding induces dissociation of the multimeric form of HIV-1 integrase: A time-resolved fluorescence anisotropy study

Deprez

Tauc

Leh

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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Self-assembly of HIV-1 integrase (IN) in solution has been studied previously by time-resolved fluorescence, using tryptophan anisotropy decay. This approach provides information on the size of macromolecules via the determination of rotational correlation times ( ). We have shown that, at submicromolar concentration, IN is characterized by a long rotational correlation time ( 20°C ‫؍‬ 90 -100 ns) corresponding to a high-order oligomeric form, likely a tetramer. In the present work, we investigated the self-assembly properties of the DNA-bound IN by using three independent fluorophores. Under enzymatic assay conditions (10 ؊7 M IN, 2 ؋ 10 ؊8 M DNA), using either fluorescein-labeled or fluorescent guanosine analog-containing oligonucleotides that mimic a viral end long terminal repeat sequence, we found that the DNA- I ntegration of a DNA copy of the HIV-1 genome into the host genome is a critical step of the retrovirus life cycle. Integration is a multistep process including 3Ј processing, strand transfer, and DNA repair. Integrase (IN) is responsible for 3Ј processing and strand transfer and is sufficient to catalyze these two reactions in vitro, using short-length oligonucleotides (ODNs) that mimic the viral end long terminal repeat sequences. The repair step most likely is performed by a host system. IN is a member of the superfamily of polynucleotidyl transferases, and its catalytic core domain contains a triad of acidic residues that constitute the so-called D,D-35-E motif. This motif is strictly required for catalysis (1, 2) and is involved in the coordination of the metal cation cofactor (3, 4). Catalysis can be performed efficiently in vitro by using either Mn 2ϩ or Mg 2ϩ , but several investigations suggest that these two divalent cations have different effects on the reaction specificity. Specific protein-DNA contacts occur preferentially in the presence of Mg 2ϩ (5), and more nonspecific cleavage is detected in the presence of Mn 2ϩ (6). The transfer pattern on the target DNA also depends on the nature of the cation (7). Consequently, the efficiency of inhibitors can be different by using either Mg 2ϩ or Mn 2ϩ in assays (8). In each case, the Mg 2ϩ -dependent activity may be more reliable because it is more physiologically relevant.Specific recognition between IN and the substrate viral DNA is a prerequisite for the cleavage of two nucleotides at the 3Ј end of the viral DNA. The catalytic core domain establishes specific contacts with the viral DNA, and it has been determined that the terminal 13-base region of the long terminal repeat plays a significant role for Mg 2ϩ -dependent processing in terms of specificity (5, 9). The C-terminal domain also mediates viral DNA-IN interactions, but in a nonspecific fashion, and more likely contributes to complex stabilization (10-12). Furthermore, it is strongly believed that self-association of IN plays a key role in governing the enzyme function (13-16). Recently, we have shown that the capability of IN to use Mg 2ϩ is related to the protein self-association ...

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A New Class of HIV-1 Integrase Inhibitors: The 3,3,3‘,3‘-Tetramethyl-1,1‘-spirobi(indan)-5,5‘,6,6‘-tetrol Family

Cited by 56 publications

References 102 publications

Gold Catalysis: Domino Reaction of En‐Diynes to Highly Substituted Phenols

Gold Catalysis: Domino Reaction of En‐Diynes to Highly Substituted Phenols

Integrase and integration: biochemical activities of HIV-1 integrase

DNA binding induces dissociation of the multimeric form of HIV-1 integrase: A time-resolved fluorescence anisotropy study

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