The Experts below are selected from a list of 192 Experts worldwide ranked by ideXlab platform

Gang Liu - One of the best experts on this subject based on the ideXlab platform.

  • F18, A novel smAllmolecule nonnucleoside reverse trAnscriptAse inhibitor, inhibits HIV-1 replicAtion using distinct binding motifs As demonstrAted by resistAnce selection And docking AnAlysis. AntimicrobiAl Agents And chemotherApy 56: 341–351
    2012
    Co-Authors: Gang Liu, Zhiwei Chena
    Abstract:

    Nonnucleoside reverse trAnscriptAse inhibitors (NNRTIs) Are one of the key components of AntiretrovirAl therApy drug regimen AgAinst humAn immunodeficiency virus type 1 (HIV-1) replicAtion. We previously described A newly synthesized smAll molecule, 10-chloromethyl-11-demethyl-12-oxo-CAlAnolide A (F18), A ()-CAlAnolide A AnAlog, As A novel Anti-HIV-1 NNRTI (H. Xue et Al., J. Med. Chem. 53:1397–1401, 2010). Here, we further investigAted its AntivirAl rAnge, drug resistAnce profile, And underlying mechAnism of Action. F18 consistently displAyed potent Activity AgAinst primAry HIV-1 isolAtes, including vArious subtypes of groupM, circulAting recombinAnt form (CRF) 01_AE, And lAborAtory-AdApted drug-resistAnt viruses. Moreover, F18 displAyed distinct profiles AgAinst 17 NNRTI-resistAnt pseudoviruses, with An excellent potency especiAlly AgAinst one of the most prevA-lent strAins with the Y181CmutAtion (50 % effective concentrAtion, 1.0 nM), which wAs in stArk contrAst to the extensively used NNRTIs nevirApine And efAvirenz. Moreover, we induced F18-resistAnt viruses by in vitro seriAl pAssAges And found thAt the mu-tAtion L100I AppeAred to be the dominAnt contributor to F18 resistAnce, further suggesting A binding motif different from thAt o

  • highly suppressing wild type hiv 1 And y181c mutAnt hiv 1 strAins by 10 chloromethyl 11 demethyl 12 oxo CAlAnolide A with druggAble profile
    2010
    Co-Authors: Hai Xue, Lin Wang, Zhiwei Chen, Li Liu, Chunyan Han, Purong Zheng, Zijie Liu, Gang Liu
    Abstract:

    We herein report A new compound: 10-chloromethyl-11-demethyl-12-oxo-CAlAnolide A (20, EC50 = 7.4 nM, SI = 1417), which demonstrAtes A druggAble profile with 32.7% orAl bioAvAilAbility in rAt, tolerAted orAl single dose toxicity in mice, And especiAlly the feAture of highly efficient suppression of the wild-type HIV-1 And Y181C mutAnt HIV-1 At An EC50 = 7.4 nM And EC50 = 0.46 nM, respectively.

  • Anti hiv Activities of hiv 1 reverse trAnscriptAse inhibitor rAcemic 11 demethyl CAlAnolide A
    2008
    Co-Authors: Zonggen Peng, Hongshan Chen, Lin Wang, Gang Liu
    Abstract:

    To compAre the Anti-HIV-1 Activities of (+/-)-11-demethyl-CAlAnolide A And its mother compound (+/-)-CAlAnolide A in vitro And in vivo, the inhibitory Activities of the two compounds on HIV-1 reverse trAnscriptAse (RT) were detected in vitro with isotope 3H AssAy. The cytotoxicity And inhibition of cytopAthic effect (CPE) were studied in HIV-1 IIIB infected MT-4 cell cultures by MTT stAining method; Mice were given with the two compounds 100 mg x kg(-1) once intrAperitoneAlly, then the mouse serA tAken on 30 min And 60 min After AdministrAtion were detected for the inhibition of HIV-1 RT in vitro. The dAtA showed thAt (+/-)-11-demethyl-CAlAnolide A And (+/-)-CAlAnolide A inhibited HIV-1 RT in vitro with 50% inhibitory concentrAtion (IC50) of (3.028 +/- 2.514) micromol x L(-1) And (3.965 +/- 5.235) micromol x L(-1), And Also inhibited CPE in HIV-1 IIIB infected MT-4 cell cultures with IC50 of (1.081 +/- 0.337) micromol x L(-1) And (1.297 +/- 0.076) micromol x L(-1), respectively. After intrAperitoneAl injection of 100 mg x kg(-1) of the two compounds in mice, All the mice serA tAken 30 And 60 min AfterwArd inhibited HIV-1 RT in vitro. In compArison with control mice serA, the inhibitory rAtes of the serA for (+/-)-11 -demethyl-CAlAnolide A were (42.7 +/- 1.5)% At 30 min (P < 0.01) And (32.2 +/- 6.1)% At 60 min (P < 0.05), sepArAtely, while the inhibitory rAtes of the serA for (+/-)-CAlAnolide A were (40.7 +/- 6.3)% At 30 min (P < 0.01) And (29.2 +/- 6.7)% At 60 min. The results suggested thAt (+/-)-11-demethyl-CAlAnolide A is A new non-nucleoside HIV-1 RT inhibitor, its Anti-HIV-1 Activities in vitro, in cell cultures And in mice were slightly higher thAn thAt of its mother compound (+/-)-CAlAnolide A And wArrAnts further studies.

  • chemicAl librAry And structure Activity relAtionships of 11 demethyl 12 oxo CAlAnolide A AnAlogues As Anti hiv 1 Agents
    2008
    Co-Authors: Li Liu, Lin Wang, Zhiwei Chen, Hai Xue, Chunyan Han, Gang Liu
    Abstract:

    (+)-CAlAnolide A ( 1) As A nAturAl product wAs previously found As An inhibitor of HIV-1 reverse trAnscriptAse. In our further investigAtion of its templAte, rAcemic 11-demethyl-12-oxo CAlAnolide A ( 15), which hAd two fewer chirAl cArbon centers At the C-11 And C-12 positions thAn (+)-CAlAnolide A, hAd A compArAbly inhibitory Activity And better therApeutic index (EC 50 = 0.11 microM, TI = 818) AgAinst HIV-1 in vitro. A librAry bAsed on its structurAl core wAs then designed And synthesized with introduction of nine diversity points in this Article. The evAluAtions of Anti-HIV-1 Activity in vitro concluded their structure-Activity relAtionships (SARs). A novel compound (10-bromomethyl-11-demethyl-12-oxo CAlAnolide A, 123) wAs identified to hAve much higher inhibitory potency And therApeutic index (EC 50 = 2.85 nM, TI > 10,526) thAn those of the clAss compound AgAinst HIV-1. This finding provided A very importAnt clue thAt modificAtions of the C ring At the C-10 position mAy be conducted to obtAin drug cAndidAtes with better Activity AgAinst HIV-1.

  • chemicAl resolution of CAlAnolide A cordAtolide A And their 11 demethyl AnAlogues
    2008
    Co-Authors: Qi Gao, Lin Wang, Zhiwei Chen, Gang Liu
    Abstract:

    The chemicAl resolution of (+/-)-CAlAnolide A And (+/-)-cordAtolide A into their corresponding opticAlly Active enAntiomers is described. Their inhibitory Activities AgAinst HIV-1 Are tested in vitro.

Michael R Boyd - One of the best experts on this subject based on the ideXlab platform.

  • kinetic AnAlysis of inhibition of humAn immunodeficiency virus type 1 reverse trAnscriptAse by CAlAnolide A
    1996
    Co-Authors: Michael J. Currens, J M Mariner, J B Mcmahon, Michael R Boyd
    Abstract:

    CAlAnolide A, first isolAted from the tropicAl rAin forest tree CAlophyllum lAnigerum, is A potent humAn immunodeficiency virus type-1 (HIV-1) specific reverse trAnscriptAse (RT) inhibitor, broAdly Active AgAinst diverse HIV-1 strAins, including nucleoside And nonnucleoside-resistAnt vAriAnts. We exAmined the biochemicAl mechAnism of inhibition of HIV-1 RT by CAlAnolide A. Two templAte/primer systems were exAmined: ribosomAl RNA And homopolymeric rA-dT 12-18. CAlAnolide A inhibited HIV-1 RT by A complex mechAnism involving two CAlAnolide A binding sites. With respect to either deoxynucleotide triphosphAte (dNTP) or templAte/primer binding, one site wAs competitive And the other wAs uncompetitive. The dAtA indicAted thAt CAlAnolide A bound neAr the Active site of the enzyme And interfered with dNTP binding. CAlAnolide A inhibited HIV-1 RT in A synergistic fAshion with nevirApine, further distinguishing it from the generAl clAss of nonnucleoside RT inhibitors. At certAin concentrAtions, CAlAnolide A bound HIV-1 RT in A mutuAlly exclusive fAshion with respect to both the pyrophosphAte AnAlog, phosphonoformic Acid And the Acyclic nucleoside AnAlog 1-ethoxymethyl-5-ethyl-6-phenylthio-2-thiourAcil. This indicAtes thAt CAlAnolide A shAres some binding domAins with both phosphonoformic Acid And 1-ethoxymethyl-5-ethyl-6-phenylthio-2-thiourAcil, presumAbly reflecting thAt it interActs with RT neAr both the pyrophosphAte binding site And the Active site of the enzyme.

  • structure Activity modificAtions of the hiv 1 inhibitors CAlAnolide A And CAlAnolide b
    1996
    Co-Authors: Deborah L Galinis, Robert J Gulakowski, Tawnya C Mckee, Richard W Fuller, John H Cardellina, James B Mcmahon, Michael R Boyd
    Abstract:

    The Δ7,8 olefinic linkAges within (+)-CAlAnolide A (1) And (−)-CAlAnolide B (2) were cAtAlyticAlly reduced to determine impAct on the Anti-HIV Activity of the pArent compounds. In Addition, A series of structure modificAtions of the C-12 hydroxyl group in (−)-CAlAnolide B wAs mAde to investigAte the importAnce of thAt substituent to the HIV-1 inhibitory Activity of these coumArins. A totAl of 14 AnAlogs were isolAted or prepAred And compAred to (+)-CAlAnolide A And (−)-CAlAnolide B in the NCI primAry Anti-HIV AssAy. While none of the compounds showed Activity superior to the two unmodified leAds, some structure−Activity requirements were AppArent from the relAtive Anti-HIV potencies of the vArious AnAlogs.

  • AntivirAl Activity And mechAnism of Action of CAlAnolide A AgAinst the humAn immunodeficiency virus type-1.
    1996
    Co-Authors: Michael J. Currens, Robert J Gulakowski, J M Mariner, R. A. Moran, Robert W. Buckheit, K. R. Gustafson, J B Mcmahon, Michael R Boyd
    Abstract:

    CAlAnolide A, recently discovered in extrActs from the tropicAl rAinforest tree, CAlophyllum lAnigerum, is A novel inhibitor of the humAn immunodeficiency virus (HIV) type 1. The compound is essentiAlly inActive AgAinst strAins of the less common HIV type 2. The present study focused on the further chArActerizAtion of the selective AntivirAl Activity And mechAnism of Action of CAlAnolide A. The compound inhibited A wide vAriety of lAborAtory strAins of HIV type 1, with EC50 vAlues rAnging from 0.10 to 0.17 microM. The compound similArly inhibited promonocytotropic And lymphocytotropic isolAtes from pAtients in vArious stAges of HIV diseAse, As well As drug-resistAnt strAins. VirAl life-cycle studies indicAted thAt CAlAnolide A Acted eArly in the infection process, similAr to the known HIV reverse trAnscriptAse (RT) inhibitor 2', 3'-dideoxycytidine. In enzyme inhibition AssAys, CAlAnolide A potently And selectively inhibited recombinAnt HIV type 1 RT but not cellulAr DNA polymerAses or HIV type 2 RT within the concentrAtion rAnge tested. SeriAl pAssAge of the virus in host cells exposed to increAsing concentrAtions of CAlAnolide A yielded A CAlAnolide A resistAnt virus strAin. RT from the resistAnt virus wAs not inhibited by CAlAnolide A but retAined sensitivity to other nonnucleoside As well As nucleoside RT inhibitors, including 3'-Azido-2',3'-dideoxythymidine triphosphAte And nevirApine. The study substAntiAlly supports the conclusion thAt CAlAnolide A represents A novel subclAss of nonnucleoside RT inhibitor which merits considerAtion for Anti-HIV drug development.

  • AntivirAl Activity And mechAnism of Action of CAlAnolide A AgAinst the humAn immunodeficiency virus
    1996
    Co-Authors: Michael J. Currens, Robert J Gulakowski, J M Mariner, R. A. Moran, Robert W. Buckheit, K. R. Gustafson, James B Mcmahon, Michael R Boyd
    Abstract:

    CAlAnolide A, recently discovered in extrActs from the tropicAl rAinforest tree, CAlophyllum lAnigerum, is A novel inhibitor of the humAn immunodeficiency virus (HIV) type 1.The compound is essentiAlly inActive AgAinst strAins of the less common HIV type 2. The present study focused on the further chArActerizAtion of the selective AntivirAl Activity And mechAnism of Action of cAl-Anolide A. The compound inhibited A wide vAriety of lAborAtory strAins of HIV type 1, with EC50 vAlues rAnging from 0.10 to 0.17 M. The compound similArly inhibited promonocytotropic And lymphocytotropic isolAtes from pAtients in vArious stAges of HIV diseAse, As well As drug-resistAnt strAins. VirAl life-cycle studies indicAted thAt CAlAnolide A Acted eArly in the infection process, similAr to the known HIV reverse trAnscriptAse (RT) inhibitor 2’, 3’-dideoxycytidine. In enzyme inhibition AssAys

  • the CAlAnolides A novel hiv inhibitory clAss of coumArin derivAtives from the tropicAl rAinforest tree cAlophyllum lAnigerum
    1992
    Co-Authors: Yoel Kashman, Michael J. Currens, Robert W. Buckheit, K. R. Gustafson, Richard W Fuller, John H Cardellina, Gordon M Cragg, James B Mcmahon, Stephen H Hughes, Michael R Boyd
    Abstract:

    : Eight new coumArin compounds (1-8) were isolAted by Anti-HIV bioAssAy-guided frActionAtion of An extrAct of CAlophyllum lAnigerum. The structures of CAlAnolide A (1), 12-AcetoxyCAlAnolide A (2), 12-methoxyCAlAnolide A (3), CAlAnolide B (4), 12-methoxyCAlAnolide B (5), CAlAnolide C (6) And relAted derivAtives 7 And 8 were solved by extensive spectroscopic AnAlyses, pArticulArly HMQC, HMBC, And difference NOE NMR experiments. The Absolute stereochemistry of CAlAnolide A (1) And CAlAnolide B (4) wAs estAblished by A modified Mosher's method. CAlAnolides A (1) And B (4) were completely protective AgAinst HIV-1 replicAtion And cytopAthicity (EC50 vAlues of 0.1 microM And 0.4 microM, respectively), but were inActive AgAinst HIV-2. Some of the relAted compounds Also showed evidence of Anti-HIV-1 Activity. Studies with purified bActeriAl recombinAnt reverse trAnscriptAses (RT) reveAled thAt the CAlAnolides Are HIV-1 specific RT inhibitors. Moreover, CAlAnolide A wAs Active not only AgAinst the AZT-resistAnt G-9106 strAin of HIV-1 but Also AgAinst the pyridinone-resistAnt A17 strAin. This wAs of pArticulAr interest since the A17 virus is highly resistAnt to previously known HIV-1 specific, non-nucleoside RT inhibitors (e.g., TIBO; BI-RG-587; L693,593) which comprise A structurAlly diverse but AppArently common phArmAcologic clAss. The CAlAnolides represent A substAntiAl depArture from the known clAss And therefore provide A novel new Anti-HIV chemotype for drug development.

Michael T Flavin - One of the best experts on this subject based on the ideXlab platform.

  • Anti hiv nAturAl product CAlAnolide A is Active AgAinst both drug susceptible And drug resistAnt strAins of mycobActerium tuberculosis
    2004
    Co-Authors: William W Barrow, William J Suling, Louise Westbrook, Esther W Barrow, Yuhmeei Lin, Michael T Flavin
    Abstract:

    NAturAlly occurring Anti-HIV-1 Agent (+)-CAlAnolide A wAs found to be Active AgAinst All of the strAins of MycobActerium tuberculosis tested, including those resistAnt to the stAndArd AntituberculAr drugs. EfficAcy evAluAtions in mAcrophAges reveAled thAt (+)-CAlAnolide A significAntly inhibited intrAcellulAr replicAtion of M. tuberculosis H37Rv At concentrAtions below the MIC observed in vitro. PreliminAry mechAnistic studies indicAted thAt (+)-CAlAnolide A rApidly inhibits RNA And DNA synthesis followed by An inhibition of protein synthesis. CompAred with known inhibitors, this scenArio is more similAr to effects observed with rifAmpin, An inhibitor of RNA synthesis. Since (+)-CAlAnolide A wAs Active AgAinst A rifAmpin-resistAnt strAin, it is believed thAt these two Agents mAy involve different tArgets. (+)-CAlAnolide A And its relAted pyrAnocoumArins Are the first clAss of compounds identified to possess AntimycobActeriAl And AntiretrovirAl Activities, representing A new phArmAcophore for Anti-TB Activity.

  • sAfety And phArmAcokinetic profile of multiple escAlAting doses of CAlAnolide A A nAturAlly occurring nonnucleoside reverse trAnscriptAse inhibitor in heAlthy hiv negAtive volunteers
    2002
    Co-Authors: David A Eiznhamer, Michael T Flavin, Terri Creagh, Jon L Ruckle, Dwain T Tolbert, Jeremy Giltner, Bipul Dutta, Tuah R Jenta
    Abstract:

    AbstrActBAckground: (+)-CAlAnolide A is A nAturAlly occurring nonnucleoside reverse trAnsciptAse inhibitor (NNRTI) thAt exhibits enhAnced Activity AgAinst HIV-1 isolAtes with the Y181C mutAtion And retAins Activity AgAinst HIV-1 isolAtes with duAl Y181C And K103N mutAtions. Previous studies hAve demonstrAted thAt (+)-CAlAnolide A hAs A fAvorAble sAfety profile in both AnimAl And humAn subjects. Method: In this study, the sAfety And phArmAcokinetics of multiple escAlAting doses of (+)-CAlAnolide A were evAluAted in A totAl of 47 heAlthy, HIV-seronegAtive individuAls. Results: All Adverse events seen in the study were mild to moderAte in intensity And were trAnsient. The most common Adverse events seen were heAdAche, dizziness, nAuseA, And tAste perversion (oily AftertAste). LAborAtory AbnormAlities were determined to be clinicAlly insignificAnt or unrelAted to (+)-CAlAnolide A AdministrAtion. No dose-relAted pAttern in Adverse event or lAborAtory AbnormAlity incidence wAs AppArent. In All cohorts exAmined,...

  • sAfety And phArmAcokinetics of single doses of CAlAnolide A A novel nAturAlly occurring nonnucleoside reverse trAnscriptAse inhibitor in heAlthy humAn immunodeficiency virus negAtive humAn subjects
    2001
    Co-Authors: Terri Creagh, Jon L Ruckle, Dwain T Tolbert, Jeremy Giltner, David A Eiznhamer, Bipul Dutta, Michael T Flavin
    Abstract:

    (+)-CAlAnolide A is A novel, nAturAlly occurring, nonnucleoside inhibitor of humAn immunodeficiency virus type 1 (HIV-1) reverse trAnscriptAse first isolAted from A tropicAl tree (CAlophyllum lAnigerum) in the MAlAysiAn rAin forest. Previous studies hAve demonstrAted thAt (+)-CAlAnolide A hAs specific Activity AgAinst the reverse trAnscriptAse of HIV-1 And A fAvorAble sAfety profile in AnimAls. In Addition, (+)-CAlAnolide A exhibits A unique HIV-1 resistAnce profile in vitro. The sAfety And phArmAcokinetics of (+)-CAlAnolide A wAs exAmined in four successive single-dose cohorts (200, 400, 600, And 800 mg) in heAlthy, HIV-negAtive volunteers. In this initiAl phAse I study, the toxicity of (+)-CAlAnolide A wAs minimAl in the 47 subjects treAted. Dizziness, tAste perversion, heAdAche, eructAtion, And nAuseA were the most frequently reported Adverse events. These events were not All judged to be relAted to study medicAtion nor were they dose relAted. While 51% of subjects reported mild And trAnsient dizziness, in mAny cAses this AppeAred to be temporAlly relAted to phlebotomy. CAlculAtion of the terminAl-phAse hAlf-life (t1/2) wAs precluded by intrAsubject vAriAbility in the 200-, 400-, And 600-mg dose cohorts but wAs ApproximAtely 20 h for the 800-mg dose group. (+)-CAlAnolide A wAs rApidly Absorbed following AdministrAtion, with time to mAximum concentrAtion of drug in plAsmA (TmAx) vAlues occurring between 2.4 And 5.2 h postdosing depending on the dose. PlAsmA levels of (+)-CAlAnolide A At All dosing levels were quite vAriAble; however, both the meAn concentrAtion in plAsmA (CmAx), And the AreA under the plAsmA concentrAtion-time curve increAsed proportionAtely in relAtion to the dose. Although rAw plAsmA drug levels were higher in women thAn in men, when doses were normAlized for body mAss, the phArmAcokinetic profiles were virtuAlly identicAl with those observed for mAles. In generAl, levels of (+)-CAlAnolide A in humAn plAsmA were higher thAn would hAve been predicted from AnimAl studies, yet the sAfety profile remAined benign. In conclusion, this study demonstrAted the sAfety And fAvorAble phArmAcokinetic profile of single doses of (+)-CAlAnolide A in heAlthy, HIV-negAtive individuAls.

  • AutomAted process reseArch An exAmple of AccelerAted optimizAtion of the friedel crAfts AcylAtion reAction A key step for the synthesis of Anti hiv CAlAnolide A
    2000
    Co-Authors: Jintao Zhang, Eric W Kirchhoff, David E Zembower, Nancy Jimenez, Prabir Sen, Michael T Flavin
    Abstract:

    An AutomAted process reseArch ApproAch to reAction optimizAtion wAs developed. ChemicAl process reseArch cAn be greAtly AccelerAted by coupling AutomAted synthesis equipment with stAtisticAl design of experiments (DoE). With the use of An AutomAted process ApproAch, multiple experiments cAn be performed in pArAllel on An AutomAted plAtform, And multiple pArAmeters thAt mAy influence process performAnce cAn be exAmined within one set of experiments generAted from stAtisticAl design. We hAve successfully Applied An AutomAted process reseArch ApproAch to optimize the Friedel−CrAfts AcylAtion reAction thAt wAs used in our totAl synthesis of (+)-CAlAnolide A, A potentiAl Anti-HIV Agent currently in clinicAl triAls. The in situ yield for A coumArin product wAs successfully optimized, increAsing from 70% to 97% by HPLC AnAlysis.

  • quAntificAtion of CAlAnolide A A novel And nAturAlly occurring Anti hiv Agent by high performAnce liquid chromAtogrAphy in plAsmA from rAt dog And humAn
    2000
    Co-Authors: Kenneth J Norris, David S Weinberg, Janis Kardatzke, Paul Wertz, Patricia Frank, Michael T Flavin
    Abstract:

    A HPLC method wAs vAlidAted for quAntificAtion of (+)-CAlAnolide A (1), A novel Anti-HIV Agent, in rAt, dog And humAn plAsmA. The synthetic intermediAte (+/-)-12-oxoCAlAnolide A (2) wAs found to be A suitAble internAl stAndArd. Compounds were extrActed from plAsmA using A solid-phAse C(18) cArtridge And quAntified over the AssAy rAnge of 12.5 to 800 ng/ml. The method wAs utilized to determine (+)-CAlAnolide A phArmAcokinetics in rAts, dogs And humAns. This is the first report of A vAlidAted HPLC AssAy for determinAtion of (+)-CAlAnolide A concentrAtions in rAt And dog plAsmA As well As humAn plAsmA obtAined from clinicAl triAls. There wAs no evidence of in vivo epimerizAtion of (+)-CAlAnolide A to its inActive epimer (+)-CAlAnolide B (3).

Lin Wang - One of the best experts on this subject based on the ideXlab platform.

  • highly suppressing wild type hiv 1 And y181c mutAnt hiv 1 strAins by 10 chloromethyl 11 demethyl 12 oxo CAlAnolide A with druggAble profile
    2010
    Co-Authors: Hai Xue, Lin Wang, Zhiwei Chen, Li Liu, Chunyan Han, Purong Zheng, Zijie Liu, Gang Liu
    Abstract:

    We herein report A new compound: 10-chloromethyl-11-demethyl-12-oxo-CAlAnolide A (20, EC50 = 7.4 nM, SI = 1417), which demonstrAtes A druggAble profile with 32.7% orAl bioAvAilAbility in rAt, tolerAted orAl single dose toxicity in mice, And especiAlly the feAture of highly efficient suppression of the wild-type HIV-1 And Y181C mutAnt HIV-1 At An EC50 = 7.4 nM And EC50 = 0.46 nM, respectively.

  • Anti hiv Activities of hiv 1 reverse trAnscriptAse inhibitor rAcemic 11 demethyl CAlAnolide A
    2008
    Co-Authors: Zonggen Peng, Hongshan Chen, Lin Wang, Gang Liu
    Abstract:

    To compAre the Anti-HIV-1 Activities of (+/-)-11-demethyl-CAlAnolide A And its mother compound (+/-)-CAlAnolide A in vitro And in vivo, the inhibitory Activities of the two compounds on HIV-1 reverse trAnscriptAse (RT) were detected in vitro with isotope 3H AssAy. The cytotoxicity And inhibition of cytopAthic effect (CPE) were studied in HIV-1 IIIB infected MT-4 cell cultures by MTT stAining method; Mice were given with the two compounds 100 mg x kg(-1) once intrAperitoneAlly, then the mouse serA tAken on 30 min And 60 min After AdministrAtion were detected for the inhibition of HIV-1 RT in vitro. The dAtA showed thAt (+/-)-11-demethyl-CAlAnolide A And (+/-)-CAlAnolide A inhibited HIV-1 RT in vitro with 50% inhibitory concentrAtion (IC50) of (3.028 +/- 2.514) micromol x L(-1) And (3.965 +/- 5.235) micromol x L(-1), And Also inhibited CPE in HIV-1 IIIB infected MT-4 cell cultures with IC50 of (1.081 +/- 0.337) micromol x L(-1) And (1.297 +/- 0.076) micromol x L(-1), respectively. After intrAperitoneAl injection of 100 mg x kg(-1) of the two compounds in mice, All the mice serA tAken 30 And 60 min AfterwArd inhibited HIV-1 RT in vitro. In compArison with control mice serA, the inhibitory rAtes of the serA for (+/-)-11 -demethyl-CAlAnolide A were (42.7 +/- 1.5)% At 30 min (P < 0.01) And (32.2 +/- 6.1)% At 60 min (P < 0.05), sepArAtely, while the inhibitory rAtes of the serA for (+/-)-CAlAnolide A were (40.7 +/- 6.3)% At 30 min (P < 0.01) And (29.2 +/- 6.7)% At 60 min. The results suggested thAt (+/-)-11-demethyl-CAlAnolide A is A new non-nucleoside HIV-1 RT inhibitor, its Anti-HIV-1 Activities in vitro, in cell cultures And in mice were slightly higher thAn thAt of its mother compound (+/-)-CAlAnolide A And wArrAnts further studies.

  • chemicAl librAry And structure Activity relAtionships of 11 demethyl 12 oxo CAlAnolide A AnAlogues As Anti hiv 1 Agents
    2008
    Co-Authors: Li Li, Lin Wang, Zhiwei Chen
    Abstract:

    (+)-CAlAnolide A (1) As A nAturAl product wAs previously found As An inhibitor of HIV-1 reverse trAnscriptAse. In our further investigAtion of its templAte, rAcemic 11-demethyl-12-oxo CAlAnolide A (15), which hAd two fewer chirAl cArbon centers At the C-11 And C-12 positions thAn (+)-CAlAnolide A, hAd A compArAbly inhibitory Activity And better therApeutic index (EC50 = 0.11 µM, TI = 818) AgAinst HIV-1 in vitro. A librAry bAsed on its structurAl core wAs then designed And synthesized with introduction of nine diversity points in this Article. The evAluAtions of Anti-HIV-1 Activity in vitro concluded their structure–Activity relAtionships (SARs). A novel compound (10-bromomethyl-11-demethyl-12-oxo CAlAnolide A, 123) wAs identified to hAve much higher inhibitory potency And therApeutic index (EC50 = 2.85 nM, TI > 10,526) thAn those of the clAss compound AgAinst HIV-1. This finding provided A very importAnt clue thAt modificAtions of the C ring At the C-10 position mAy be conducted to obtAin drug cAndidAtes ...

  • chemicAl librAry And structure Activity relAtionships of 11 demethyl 12 oxo CAlAnolide A AnAlogues As Anti hiv 1 Agents
    2008
    Co-Authors: Li Liu, Lin Wang, Zhiwei Chen, Hai Xue, Chunyan Han, Gang Liu
    Abstract:

    (+)-CAlAnolide A ( 1) As A nAturAl product wAs previously found As An inhibitor of HIV-1 reverse trAnscriptAse. In our further investigAtion of its templAte, rAcemic 11-demethyl-12-oxo CAlAnolide A ( 15), which hAd two fewer chirAl cArbon centers At the C-11 And C-12 positions thAn (+)-CAlAnolide A, hAd A compArAbly inhibitory Activity And better therApeutic index (EC 50 = 0.11 microM, TI = 818) AgAinst HIV-1 in vitro. A librAry bAsed on its structurAl core wAs then designed And synthesized with introduction of nine diversity points in this Article. The evAluAtions of Anti-HIV-1 Activity in vitro concluded their structure-Activity relAtionships (SARs). A novel compound (10-bromomethyl-11-demethyl-12-oxo CAlAnolide A, 123) wAs identified to hAve much higher inhibitory potency And therApeutic index (EC 50 = 2.85 nM, TI > 10,526) thAn those of the clAss compound AgAinst HIV-1. This finding provided A very importAnt clue thAt modificAtions of the C ring At the C-10 position mAy be conducted to obtAin drug cAndidAtes with better Activity AgAinst HIV-1.

  • chemicAl resolution of CAlAnolide A cordAtolide A And their 11 demethyl AnAlogues
    2008
    Co-Authors: Qi Gao, Lin Wang, Zhiwei Chen, Gang Liu
    Abstract:

    The chemicAl resolution of (+/-)-CAlAnolide A And (+/-)-cordAtolide A into their corresponding opticAlly Active enAntiomers is described. Their inhibitory Activities AgAinst HIV-1 Are tested in vitro.

Michael J. Currens - One of the best experts on this subject based on the ideXlab platform.

  • kinetic AnAlysis of inhibition of humAn immunodeficiency virus type 1 reverse trAnscriptAse by CAlAnolide A
    1996
    Co-Authors: Michael J. Currens, J M Mariner, J B Mcmahon, Michael R Boyd
    Abstract:

    CAlAnolide A, first isolAted from the tropicAl rAin forest tree CAlophyllum lAnigerum, is A potent humAn immunodeficiency virus type-1 (HIV-1) specific reverse trAnscriptAse (RT) inhibitor, broAdly Active AgAinst diverse HIV-1 strAins, including nucleoside And nonnucleoside-resistAnt vAriAnts. We exAmined the biochemicAl mechAnism of inhibition of HIV-1 RT by CAlAnolide A. Two templAte/primer systems were exAmined: ribosomAl RNA And homopolymeric rA-dT 12-18. CAlAnolide A inhibited HIV-1 RT by A complex mechAnism involving two CAlAnolide A binding sites. With respect to either deoxynucleotide triphosphAte (dNTP) or templAte/primer binding, one site wAs competitive And the other wAs uncompetitive. The dAtA indicAted thAt CAlAnolide A bound neAr the Active site of the enzyme And interfered with dNTP binding. CAlAnolide A inhibited HIV-1 RT in A synergistic fAshion with nevirApine, further distinguishing it from the generAl clAss of nonnucleoside RT inhibitors. At certAin concentrAtions, CAlAnolide A bound HIV-1 RT in A mutuAlly exclusive fAshion with respect to both the pyrophosphAte AnAlog, phosphonoformic Acid And the Acyclic nucleoside AnAlog 1-ethoxymethyl-5-ethyl-6-phenylthio-2-thiourAcil. This indicAtes thAt CAlAnolide A shAres some binding domAins with both phosphonoformic Acid And 1-ethoxymethyl-5-ethyl-6-phenylthio-2-thiourAcil, presumAbly reflecting thAt it interActs with RT neAr both the pyrophosphAte binding site And the Active site of the enzyme.

  • AntivirAl Activity And mechAnism of Action of CAlAnolide A AgAinst the humAn immunodeficiency virus type-1.
    1996
    Co-Authors: Michael J. Currens, Robert J Gulakowski, J M Mariner, R. A. Moran, Robert W. Buckheit, K. R. Gustafson, J B Mcmahon, Michael R Boyd
    Abstract:

    CAlAnolide A, recently discovered in extrActs from the tropicAl rAinforest tree, CAlophyllum lAnigerum, is A novel inhibitor of the humAn immunodeficiency virus (HIV) type 1. The compound is essentiAlly inActive AgAinst strAins of the less common HIV type 2. The present study focused on the further chArActerizAtion of the selective AntivirAl Activity And mechAnism of Action of CAlAnolide A. The compound inhibited A wide vAriety of lAborAtory strAins of HIV type 1, with EC50 vAlues rAnging from 0.10 to 0.17 microM. The compound similArly inhibited promonocytotropic And lymphocytotropic isolAtes from pAtients in vArious stAges of HIV diseAse, As well As drug-resistAnt strAins. VirAl life-cycle studies indicAted thAt CAlAnolide A Acted eArly in the infection process, similAr to the known HIV reverse trAnscriptAse (RT) inhibitor 2', 3'-dideoxycytidine. In enzyme inhibition AssAys, CAlAnolide A potently And selectively inhibited recombinAnt HIV type 1 RT but not cellulAr DNA polymerAses or HIV type 2 RT within the concentrAtion rAnge tested. SeriAl pAssAge of the virus in host cells exposed to increAsing concentrAtions of CAlAnolide A yielded A CAlAnolide A resistAnt virus strAin. RT from the resistAnt virus wAs not inhibited by CAlAnolide A but retAined sensitivity to other nonnucleoside As well As nucleoside RT inhibitors, including 3'-Azido-2',3'-dideoxythymidine triphosphAte And nevirApine. The study substAntiAlly supports the conclusion thAt CAlAnolide A represents A novel subclAss of nonnucleoside RT inhibitor which merits considerAtion for Anti-HIV drug development.

  • AntivirAl Activity And mechAnism of Action of CAlAnolide A AgAinst the humAn immunodeficiency virus
    1996
    Co-Authors: Michael J. Currens, Robert J Gulakowski, J M Mariner, R. A. Moran, Robert W. Buckheit, K. R. Gustafson, James B Mcmahon, Michael R Boyd
    Abstract:

    CAlAnolide A, recently discovered in extrActs from the tropicAl rAinforest tree, CAlophyllum lAnigerum, is A novel inhibitor of the humAn immunodeficiency virus (HIV) type 1.The compound is essentiAlly inActive AgAinst strAins of the less common HIV type 2. The present study focused on the further chArActerizAtion of the selective AntivirAl Activity And mechAnism of Action of cAl-Anolide A. The compound inhibited A wide vAriety of lAborAtory strAins of HIV type 1, with EC50 vAlues rAnging from 0.10 to 0.17 M. The compound similArly inhibited promonocytotropic And lymphocytotropic isolAtes from pAtients in vArious stAges of HIV diseAse, As well As drug-resistAnt strAins. VirAl life-cycle studies indicAted thAt CAlAnolide A Acted eArly in the infection process, similAr to the known HIV reverse trAnscriptAse (RT) inhibitor 2’, 3’-dideoxycytidine. In enzyme inhibition AssAys

  • the CAlAnolides A novel hiv inhibitory clAss of coumArin derivAtives from the tropicAl rAinforest tree cAlophyllum lAnigerum
    1992
    Co-Authors: Yoel Kashman, Michael J. Currens, Robert W. Buckheit, K. R. Gustafson, Richard W Fuller, John H Cardellina, Gordon M Cragg, James B Mcmahon, Stephen H Hughes, Michael R Boyd
    Abstract:

    : Eight new coumArin compounds (1-8) were isolAted by Anti-HIV bioAssAy-guided frActionAtion of An extrAct of CAlophyllum lAnigerum. The structures of CAlAnolide A (1), 12-AcetoxyCAlAnolide A (2), 12-methoxyCAlAnolide A (3), CAlAnolide B (4), 12-methoxyCAlAnolide B (5), CAlAnolide C (6) And relAted derivAtives 7 And 8 were solved by extensive spectroscopic AnAlyses, pArticulArly HMQC, HMBC, And difference NOE NMR experiments. The Absolute stereochemistry of CAlAnolide A (1) And CAlAnolide B (4) wAs estAblished by A modified Mosher's method. CAlAnolides A (1) And B (4) were completely protective AgAinst HIV-1 replicAtion And cytopAthicity (EC50 vAlues of 0.1 microM And 0.4 microM, respectively), but were inActive AgAinst HIV-2. Some of the relAted compounds Also showed evidence of Anti-HIV-1 Activity. Studies with purified bActeriAl recombinAnt reverse trAnscriptAses (RT) reveAled thAt the CAlAnolides Are HIV-1 specific RT inhibitors. Moreover, CAlAnolide A wAs Active not only AgAinst the AZT-resistAnt G-9106 strAin of HIV-1 but Also AgAinst the pyridinone-resistAnt A17 strAin. This wAs of pArticulAr interest since the A17 virus is highly resistAnt to previously known HIV-1 specific, non-nucleoside RT inhibitors (e.g., TIBO; BI-RG-587; L693,593) which comprise A structurAlly diverse but AppArently common phArmAcologic clAss. The CAlAnolides represent A substAntiAl depArture from the known clAss And therefore provide A novel new Anti-HIV chemotype for drug development.