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Fatih M. Uckun - One of the best experts on this subject based on the ideXlab platform.
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Stampidine as a novel nucleoside reverse transcriptase inhibit with potent Anti-HIV activity.
Arzneimittel-Forschung, 2006Co-Authors: Fatih M. UckunAbstract:Stavudine (STV, d4T, 2',3'-didehydro-3'-deoxythymidine, CAS 3056-17-5) is a standard Anti-HIV drug. Stampidine (STAMP, DDE-113, HI-113, N-[p-(4-bromophenyl)-2',3'-didehydro-3'-deoxy-5'-thymidylyl]-L-alanine methyl ester, CAS 217178-62-6) is a novel aryl phosphate derivative of stavudine with more potent Anti-HIV activity and more favorable pharmacodynamic features. The remarkable potency of stampidine against clinical HIV-1 isolates with NRTI- or NNRTI-resistance (NRTI, nucleoside reverse transcriptase inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor) warrants the further development of this new Anti-HIV Agent.
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Large-scale synthesis and formulation of GMP-grade stampidine, a new Anti-HIV Agent.
Arzneimittel-Forschung, 2006Co-Authors: Darin Dumez, Taracad K Venkatachalam, Fatih M. UckunAbstract:The arylphosphoramidate derivative of stavudine (STV, d4T, 2,3'-didehydro-3'-deoxythymidine, CAS 3056-17-5), stampidine (STAMP, DDE-113, HI-113, N-[p-(4-bromophenyl)-2',3'-didehydro-3'-deoxy-5'-thymidylyl]-L-alanine methyl ester, CAS 217178-62-6), is a novel Anti-HIV Agent. STAMP was prepared under current Good Manufacturing Practice (cGMP) conditions on the scale of kilograms. Solid STAMP was subsequently formulated as a capsule under GMP conditions for oral administration.
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In vivo evaluation of a gel formulation of stampidine, a novel nonspermicidal broad-spectrum Anti-HIV microbicide
American Journal of Drug Delivery, 2003Co-Authors: Osmond J. D’cruz, Barbara Waurzyniak, Peter Samuel, Fatih M. UckunAbstract:Introduction Stampidine (2′,3′-didehydro-2′,3′-dideoxythymidine 5′-[ p -bromophenyl methoxyalaninyl phosphate]), a novel aryl phosphate derivative of stavudine (STV/d4T), is a potent, broad-spectrum Anti-HIV Agent with potential as a new class of nonspermicidal microbicide. As part of an effort to develop an acceptable formulation for the clinical use of stampidine as a microbicide, we developed a vaginal gel formulation of stampidine and evaluated its potential to cause mucosal toxicity in the New Zealand white rabbit vaginal irritation model. Methods Stampidine was solubilized in a gel formulation composed of microcrystalline cellulose, xanthan gum, macrogol (polyethylene glycol [PEG]) 400, sorbitol, and polysorbate 80. Rabbits in groups of four were exposed intravaginally to a gel with 0.5, 1, or 2% stampidine or no active drug for 14 consecutive days. The rabbits were euthanized on day 15 and their vaginal tissues were evaluated for histologic evidence of mucosal toxicity and immunohistochemical evidence of cellular inflammation or hyperplasia. Additionally, rabbits in groups of three were exposed intravaginally to a 2% stampidine gel, and plasma samples collected at various timepoints were assayed for stampidine and its major metabolites, alaninyl-stavudine-monophosphate and stavudine by analytical high performance liquid chromatography (HPLC). Results With application of 0.5–2.0% stampidine, only minimal-to-mild vaginal irritation was observed, which is within the acceptable range for clinical trials (total score
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two year toxicity and carcinogenicity studies in b6c3f1 mice with 5 bromo 6 methoxy 5 6 dihydro 3 azidothymidine 5 p bromophenyl methoxyalaninyl phosphate whi 07 a novel anti hiv and contraceptive Agent
Toxicology, 2002Co-Authors: Osmond J Dcruz, Barbara Waurzyniak, Douglas Erbeck, Fatih M. UckunAbstract:The zidovudine derivative, 5-bromo-6-methoxy-5,6-dihydro-3′-azidothymidine-5′-(p-bromophenyl) methoxy alaninyl phosphate (WHI-07), is a dual-function spermicidal and Anti-HIV Agent with contraceptive and microbicidal activity. In previous two subchronic toxicity studies, intravaginal application of 0.5–2.0% WHI-07, for up to 13 weeks, was shown to cause no local, systemic or reproductive toxicity. To evaluate the toxicity and carcinogenic potential of long-term exposure to WHl-07, groups of 50 female B6C3F1 mice were given no treatment or exposed intravaginally to a gel-microemulsion formulation with and without 2.0% WHI-07, 5 days per week for 2 years. The dose of WHI-07 was equivalent to 5700 times its spermicidal EC50 and 5.7×106 times its Anti-HIV IC50. The endpoints that were evaluated included survival, body weight, hematologic and clinical chemistry profiles, absolute and relative organ weights, and histopathology. No significant differences in mean body weight gain and survival were found among the groups of untreated control, placebo control, and 2% WHI-07-treated mice at the end of the 2-year study. The hematological and clinical chemistry profiles did not reveal any toxicologically significant changes that could be attributed to WHI-07 treatment. No clinically significant changes in absolute and relative organ weights were noted in the WHI-07 group. A variety of neoplastic and nonneoplastic lesions which were considered incidental, related to aging, or procedural, were observed in both the untreated and intravaginally treated groups. The proportion of animals with malignant tumors, the total number of malignant tumors, as well as the types of malignant tumors in the three groups was similar. The cumulative incidence of microscopic lesions in various organs showed that malignant lymphoma was the major cause of death in aging female B6C3F1 mice, the incidence of which was unaffected by intravaginal treatment. We conclude that long-term intravaginal administration of WHI-07 is not associated with systemic toxicity or increased carcinogenicity in mice. WHI-07 has clinical potential as an active ingredient of a safe vaginal/rectal microbicide.
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synthesis characterization and preclinical formulation of a dual action phenyl phosphate derivative of bromo methoxy zidovudine compound whi 07 with potent anti hiv and spermicidal activities
Molecular Human Reproduction, 1999Co-Authors: Osmond J Dcruz, Chun-lin Chen, Meijue Shih, Fatih M. UckunAbstract:In a systematic effort to develop a microbicide contraceptive capable of preventing transmission of human immunodeficiency virus (HIV), as well as providing fertility control, we have previously identified novel phenyl phosphate derivatives of zidovudine (ZDV) with 5-halo 6-alkoxy substitutions in the thymine ring and halo substitution in the phenyl moiety respectively. Here, we describe the synthesis, characterization, and successful preclinical formulation of our lead compound, 5-bromo-6-methoxy-39-azidothymidine-59-(p-bromophenyl) methoxyalaninyl phosphate (WHI-07), which exhibits potent Anti-HIV and sperm immobilizing activities. The Anti-HIV activity of WHI-07 was tested by measuring viral p24 antigen production and reverse transcriptase activity as markers of viral replication in HIV-1 infected human peripheral blood mononuclear cells (PBMC). WHI-07 inhibited replication of HIV in a concentration-dependent fashion with nanomolar IC50 values. The effects of WHI-07 on human sperm motion kinematics were analysed by computer-assisted sperm analysis (CASA), and its effects on sperm membrane integrity were examined by confocal laser scanning microscopy (CLSM), and high-resolution low-voltage scanning electron microscopy (HR-LVSEM). WHI-07 caused cessation of sperm motility in a concentration- and time-dependent fashion. The in-vitro cytotoxicities of WHI-07 and nonoxynol-9 (N-9) were compared using normal human ectocervical and endocervical epithelial cells by the MTT cell viability assay. Unlike N-9, WHI-07 had no effect upon sperm plasma and acrosomal membrane integrity. N-9 was cytotoxic to normal human ectocervical and endocervical cells at spermicidal doses, whereas WHI-07 was selectively spermicidal. The in-vivo vaginal absorption and vaginal toxicity of 2% gelmicroemulsion of WHI-07 was studied in the rabbit model. The sperm immobilizing activity of WHI-07 was 18-fold more potent than that of N-9. Over a 10 day period, there was no irritation or local toxicity to the vaginal epithelia or systemic absorption of WHI-07. Therefore, as a potent Anti-HIV Agent with spermicidal activity, and lack of mucosal toxicity, WHI-07 may have the clinical potential to become the active ingredient of a vaginal contraceptive for women who are at high risk for acquiring HIV by heterosexual vaginal transmission.
David M Hodgson - One of the best experts on this subject based on the ideXlab platform.
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an approach to hyperolactone c and analogues using late stage conjugate addition on an oxonium ylide derived spirofuranone
Organic and Biomolecular Chemistry, 2013Co-Authors: David M Hodgson, Elena MorenoclavijoAbstract:A stereocontrolled synthesis of norphenyl hyperolactone C together with its utility as a direct precursor to the Anti-HIV Agent hyperolactone C and analogues by addition of organolithiums, are described. Preliminary studies to access this key building block in a catalytic enantioselective manner are also reported.
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synthesis of the anti hiv Agent hyperolactone c by using oxonium ylide formation rearrangement
Chemistry: A European Journal, 2011Co-Authors: David M HodgsonAbstract:: Starting from readily available (S)-styrene oxide an asymmetric synthesis is described of the naturally occurring Anti-HIV spirolactone (-)-hyperolactone C, which possesses adjacent fully substituted stereocenters. The key step involves a stereocontrolled Rh(II) -catalysed oxonium ylide formation-[2,3] sigmatropic rearrangement of an α-diazo-β-ketoester bearing allylic ether functionality. From the resulting furanone, an acid-catalysed lactonisation and dehydrogenation gives the natural product.
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Synthesis of the Anti‐HIV Agent (−)‐Hyperolactone C by Using Oxonium Ylide Formation–Rearrangement
Chemistry: A European Journal, 2011Co-Authors: David M HodgsonAbstract:Starting from readily available (S)-styrene oxide an asymmetric synthesis is described of the naturally occurring Anti-HIV spirolactone (-)-hyperolactone C, which possesses adjacent fully substituted stereocenters. The key step involves a stereocontrolled Rh(II) -catalysed oxonium ylide formation-[2,3] sigmatropic rearrangement of an α-diazo-β-ketoester bearing allylic ether functionality. From the resulting furanone, an acid-catalysed lactonisation and dehydrogenation gives the natural product.
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Consecutive alkene cross-metathesis/oxonium ylide formation-rearrangement: synthesis of the Anti-HIV Agent hyperolactone C.
Organic letters, 2008Co-Authors: David M Hodgson, Deepshikha Angrish, Stephanie P Erickson, Johannes Kloesges, Caroline H LeeAbstract:Alpha-diazo-beta-ketoesters bearing allylic ether functionality undergo highly stereoselective Ru-carbene-catalyzed alkene cross-metathesis followed by Rh(2)(OAc)(4)-catalyzed oxonium ylide formation/[2,3] sigmatropic rearrangement in a one-flask operation and in a highly diastereoselective manner. The methodology has been demonstrated in a concise synthesis of the Anti-HIV Agent hyperolactone C.
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consecutive alkene cross metathesis oxonium ylide formation rearrangement synthesis of the anti hiv Agent hyperolactone c
Organic Letters, 2008Co-Authors: David M Hodgson, Deepshikha Angrish, Stephanie P Erickson, Johannes KloesgesAbstract:α-Diazo-β-ketoesters bearing allylic ether functionality undergo highly stereoselective Ru-carbene-catalyzed alkene cross-metathesis followed by Rh2(OAc)4-catalyzed oxonium ylide formation/[2,3] sigmatropic rearrangement in a one-flask operation and in a highly diastereoselective manner. The methodology has been demonstrated in a concise synthesis of the Anti-HIV Agent hyperolactone C.
Mark Cushman - One of the best experts on this subject based on the ideXlab platform.
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Inhibition of RANTES/CCR1-mediated chemotaxis by cosalane and related compounds.
Bioorganic & Medicinal Chemistry Letters, 2001Co-Authors: O. M. Zack Howard, Hui Fang Dong, Joost J. Oppenheim, Shabana Insaf, Kalpathy C. Santhosh, Gitendra C. Paul, Mark CushmanAbstract:Abstract The Anti-HIV Agent cosalane and several of its analogues inhibited RANTES-induced migration of human monocytes, but they did not inhibit migration induced by MIP1α or MIP1β. RANTES-induced migration of single receptor CCR1-HEK transfectants was also inhibited by the cosalanes. Acetylation of the reactive amino groups of RANTES abrogated the inhibitory activity of cosalane. The data suggest that cosalane and its structural analogues may interfere with the RANTES/CCR1 interaction by binding to RANTES.
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Correlation of Anti-HIV potency with lipophilicity in a series of cosalane analogs having normal alkenyl and phosphodiester chains as cholestane replacements.
Journal of medicinal chemistry, 1996Co-Authors: Mark CushmanAbstract:In order to define the role of the cholestane moiety in the Anti-HIV Agent cosalane, a series of cosalane analogs was synthesized in which the cholestane ring system was replaced by normal alkenyl and phosphodiester substituents having varied chain lengths and lipophilicities. The compounds containing simple alkenyl substituents were found to be more potent as inhibitors of the cytopathic effect of HIV-1 in cell culture than the phosphodiesters. In addition, the potencies of the alkene congeners correlated positively with chain length and lipophilicity of the alkene. The results indicate that the cholestane moiety of cosalane functions as a lipophilic accessory appendage to escort the dichlorodisalicylmethane pharmacophore to a lipid environment.
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Design and synthesis of cosalane, a novel Anti-HIV Agent
Bioorganic & Medicinal Chemistry Letters, 1993Co-Authors: W. Marek Golebiewski, John P. Bader, Mark CushmanAbstract:Abstract Cosalane, a novel Anti-HIV Agent having a dichlorodisalicylmethane unit linked to C-3 of cholestane by a three-carbon linker, was synthesized by a convergent route.
Osmond J Dcruz - One of the best experts on this subject based on the ideXlab platform.
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two year toxicity and carcinogenicity studies in b6c3f1 mice with 5 bromo 6 methoxy 5 6 dihydro 3 azidothymidine 5 p bromophenyl methoxyalaninyl phosphate whi 07 a novel anti hiv and contraceptive Agent
Toxicology, 2002Co-Authors: Osmond J Dcruz, Barbara Waurzyniak, Douglas Erbeck, Fatih M. UckunAbstract:The zidovudine derivative, 5-bromo-6-methoxy-5,6-dihydro-3′-azidothymidine-5′-(p-bromophenyl) methoxy alaninyl phosphate (WHI-07), is a dual-function spermicidal and Anti-HIV Agent with contraceptive and microbicidal activity. In previous two subchronic toxicity studies, intravaginal application of 0.5–2.0% WHI-07, for up to 13 weeks, was shown to cause no local, systemic or reproductive toxicity. To evaluate the toxicity and carcinogenic potential of long-term exposure to WHl-07, groups of 50 female B6C3F1 mice were given no treatment or exposed intravaginally to a gel-microemulsion formulation with and without 2.0% WHI-07, 5 days per week for 2 years. The dose of WHI-07 was equivalent to 5700 times its spermicidal EC50 and 5.7×106 times its Anti-HIV IC50. The endpoints that were evaluated included survival, body weight, hematologic and clinical chemistry profiles, absolute and relative organ weights, and histopathology. No significant differences in mean body weight gain and survival were found among the groups of untreated control, placebo control, and 2% WHI-07-treated mice at the end of the 2-year study. The hematological and clinical chemistry profiles did not reveal any toxicologically significant changes that could be attributed to WHI-07 treatment. No clinically significant changes in absolute and relative organ weights were noted in the WHI-07 group. A variety of neoplastic and nonneoplastic lesions which were considered incidental, related to aging, or procedural, were observed in both the untreated and intravaginally treated groups. The proportion of animals with malignant tumors, the total number of malignant tumors, as well as the types of malignant tumors in the three groups was similar. The cumulative incidence of microscopic lesions in various organs showed that malignant lymphoma was the major cause of death in aging female B6C3F1 mice, the incidence of which was unaffected by intravaginal treatment. We conclude that long-term intravaginal administration of WHI-07 is not associated with systemic toxicity or increased carcinogenicity in mice. WHI-07 has clinical potential as an active ingredient of a safe vaginal/rectal microbicide.
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synthesis characterization and preclinical formulation of a dual action phenyl phosphate derivative of bromo methoxy zidovudine compound whi 07 with potent anti hiv and spermicidal activities
Molecular Human Reproduction, 1999Co-Authors: Osmond J Dcruz, Chun-lin Chen, Meijue Shih, Fatih M. UckunAbstract:In a systematic effort to develop a microbicide contraceptive capable of preventing transmission of human immunodeficiency virus (HIV), as well as providing fertility control, we have previously identified novel phenyl phosphate derivatives of zidovudine (ZDV) with 5-halo 6-alkoxy substitutions in the thymine ring and halo substitution in the phenyl moiety respectively. Here, we describe the synthesis, characterization, and successful preclinical formulation of our lead compound, 5-bromo-6-methoxy-39-azidothymidine-59-(p-bromophenyl) methoxyalaninyl phosphate (WHI-07), which exhibits potent Anti-HIV and sperm immobilizing activities. The Anti-HIV activity of WHI-07 was tested by measuring viral p24 antigen production and reverse transcriptase activity as markers of viral replication in HIV-1 infected human peripheral blood mononuclear cells (PBMC). WHI-07 inhibited replication of HIV in a concentration-dependent fashion with nanomolar IC50 values. The effects of WHI-07 on human sperm motion kinematics were analysed by computer-assisted sperm analysis (CASA), and its effects on sperm membrane integrity were examined by confocal laser scanning microscopy (CLSM), and high-resolution low-voltage scanning electron microscopy (HR-LVSEM). WHI-07 caused cessation of sperm motility in a concentration- and time-dependent fashion. The in-vitro cytotoxicities of WHI-07 and nonoxynol-9 (N-9) were compared using normal human ectocervical and endocervical epithelial cells by the MTT cell viability assay. Unlike N-9, WHI-07 had no effect upon sperm plasma and acrosomal membrane integrity. N-9 was cytotoxic to normal human ectocervical and endocervical cells at spermicidal doses, whereas WHI-07 was selectively spermicidal. The in-vivo vaginal absorption and vaginal toxicity of 2% gelmicroemulsion of WHI-07 was studied in the rabbit model. The sperm immobilizing activity of WHI-07 was 18-fold more potent than that of N-9. Over a 10 day period, there was no irritation or local toxicity to the vaginal epithelia or systemic absorption of WHI-07. Therefore, as a potent Anti-HIV Agent with spermicidal activity, and lack of mucosal toxicity, WHI-07 may have the clinical potential to become the active ingredient of a vaginal contraceptive for women who are at high risk for acquiring HIV by heterosexual vaginal transmission.
Caroline H Lee - One of the best experts on this subject based on the ideXlab platform.
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Consecutive alkene cross-metathesis/oxonium ylide formation-rearrangement: synthesis of the Anti-HIV Agent hyperolactone C.
Organic letters, 2008Co-Authors: David M Hodgson, Deepshikha Angrish, Stephanie P Erickson, Johannes Kloesges, Caroline H LeeAbstract:Alpha-diazo-beta-ketoesters bearing allylic ether functionality undergo highly stereoselective Ru-carbene-catalyzed alkene cross-metathesis followed by Rh(2)(OAc)(4)-catalyzed oxonium ylide formation/[2,3] sigmatropic rearrangement in a one-flask operation and in a highly diastereoselective manner. The methodology has been demonstrated in a concise synthesis of the Anti-HIV Agent hyperolactone C.
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consecutive alkene cross metathesis oxonium ylide formation rearrangement synthesis of the anti hiv Agent hyperolactone c
Organic Letters, 2008Co-Authors: David M Hodgson, Deepshikha Angrish, Stephanie P Erickson, Johannes Kloesges, Caroline H LeeAbstract:Alpha-diazo-beta-ketoesters bearing allylic ether functionality undergo highly stereoselective Ru-carbene-catalyzed alkene cross-metathesis followed by Rh(2)(OAc)(4)-catalyzed oxonium ylide formation/[2,3] sigmatropic rearrangement in a one-flask operation and in a highly diastereoselective manner. The methodology has been demonstrated in a concise synthesis of the Anti-HIV Agent hyperolactone C.