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Fatih M. Uckun - One of the best experts on this subject based on the ideXlab platform.
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a study of the potential of the pig as a model for the vaginal irritancy of benzalkonium chloride in comparison to the nonirritant microbicide phi 443 and the spermicide Vanadocene dithiocarbamate
Toxicologic Pathology, 2005Co-Authors: Osmond J Dcruz, Douglas Erbeck, Fatih M. UckunAbstract:A porcine model was established to test the mucosal toxicity potential of a thiophene thiourea (PHI-443)-based anti-HIV microbicide and a Vanadocene-based spermicide, Vanadocene dithiocarbamate (VDDTC) in comparison to benzalkonium chloride (BZK). Nine domestic pigs (Duroc) in nonestrus stage received a single intravaginal application of 2% BZK, 2% PHI-443, or 0.1% VDDTC-containing gel. At various times after gel application, cell differentials and levels of inflammatory cytokines (IL-1β, IL-4, IL-6, IL-8, IL-10, IL-18, IFN-γ , and TNF-α) in cervicovaginal lavage (CVL) fluid were monitored by flow cytometry and ELISA, respectively. Eight pigs were exposed intravaginally to a gel with and without BZK or VDDTC for 4 consecutive days and vaginal tissues were scored histologically for inflammation using a new scoring system. Only CVL fluid from pigs exposed to BZK showed a significant increase of IL-1β, IL-8, and also IL-18 production when compared to the controls, PHI-443 or VDDTC-treated groups. Maximum levels of BZK-induced IL-1β (100-fold), IL-8 (2,500-fold), IL-18 (80-fold), and IFN-γ (10-fold) were found at 24 hours. In the in vivo porcine vaginal irritation model, increased levels of vaginal IL-1β, IL-8, and IL-18 were associated with histological changes consistent with vaginal inflammation. These results demonstrate that key cervicovaginal inflammatory cytokines are useful in vivo biomarkers for predicting the mucosal toxicity potential of vaginal products in the physiologically relevant and sensitive porcine model.
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Vaginal contraceptive activity of a chelated Vanadocene.
Contraception, 2005Co-Authors: Osmond J. D'cruz, Fatih M. UckunAbstract:Abstract Bis(cyclopentadienyl) complexes of vanadium (IV) or Vanadocenes are rapid and potent inhibitors of human sperm motility with potential as a new class of contraceptive agents. This study sought to determine the vaginal contraceptive activity of Vanadocene dithiocarbamate (VDDTC), a stable Vanadocene (IV)-chelated complex, using the standard rabbit model as well as the domestic pig as a physiologically relevant animal model for contraception. In experiment I, ovulating New Zealand White does in subgroups of eight were artificially inseminated (AI) with semen mixed with VDDTC (0.01���1 mM) or vehicle. In experiment II, ovulating does in subgroups of 18 were AI at 5 and 60 min after intravaginal application of a gel with and without 0.1% VDDTC or 2% nonoxynol-9 (N-9) (Gynol II, Ortho Pharmaceutical, Raritan, NJ), and allowed to complete term pregnancy. In experiment III, seven sexually mature Duroc gilts in standing estrus were AI with and without intravaginal application of 0.1% VDDTC gel microemulsion. Exposure of rabbit semen to VDDTC at the time of artificial insemination resulted in a dose-dependent reduction in fertility. Exposure of semen to 1 mM VDDTC led to complete inhibition of fertility as assessed by the number of embryos (control 49/94 vs. VDDTC-treated 0/117, p
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Original research article Vaginal contraceptive activity of a chelated Vanadocene
2005Co-Authors: Osmond J. D'cruz, Fatih M. UckunAbstract:Bis(cyclopentadienyl) complexes of vanadium (IV) or Vanadocenes are rapid and potent inhibitors of human sperm motility with potential as a new class of contraceptive agents. This study sought to determine the vaginal contraceptive activity of Vanadocene dithiocarbamate (VDDTC), a stable Vanadocene (IV)-chelated complex, using the standard rabbit model as well as the domestic pig as a physiologically relevant animal model for contraception. In experiment I, ovulating New Zealand White does in subgroups of eight were artificially inseminated (AI) with semen mixed with VDDTC (0.01–1 mM) or vehicle. In experiment II, ovulating does in subgroups of 18 were AI at 5 and 60 min after intravaginal application of a gel with and without 0.1% VDDTC or 2% nonoxynol-9 (N-9) (Gynol II, Ortho Pharmaceutical, Raritan, NJ), and allowed to complete term pregnancy. In experiment III, seven sexually mature Duroc gilts in standing estrus were AI with and without intravaginal application of 0.1% VDDTC gel microemulsion. Exposure of rabbit semen to VDDTC at the time of artificial insemination resulted in a dose-dependent reduction in fertility. Exposure of semen to 1 mM VDDTC led to complete inhibition of fertility as assessed by the number of embryos (control 49/94 vs. VDDTC-treated 0/117, p b .0001) or the percent embryos (52% vs. 0%, respectively) based on number of embryos to corpora lutea. Intravaginal administration of 0.1% VDDTC gel microemulsion or Gynol II prior to artificial insemination significantly inhibited term pregnancy rates (88% and 62% inhibition, respectively) when compared to control gel alone. Vanadocene dithiocarbamate gel microemulsion provided 80% inhibition of fertility even when insemination was delayed until 60 min after intravaginal application of VDDTC gel microemulsion. Rabbits that delivered litters despite intravaginal exposure of semen to VDDTC via gel microemulsion had healthy offsprings with no apparent perinatal repercussions. In domestic pigs, intravaginal applications of 0.1% VDDTC gel microemulsion prior to artificial insemination led to complete inhibition of fertility as assessed by the number of embryos (control 29/52 vs. VDDTC-treated 0/44, p b .0001) or the percent embryos (56% vs. 0%, respectively) based on the number of embryos to corpora lutea. These results suggest that VDDTC is a potent contraceptive agent in vivo. Intravaginal use of VDDTC via a gel microemulsion has clinical potential as a safe alternative to currently used detergent-type contraceptives.
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antiretroviral spermicide whi 07 prevents vaginal and rectal transmission of feline immunodeficiency virus in domestic cats
Antimicrobial Agents and Chemotherapy, 2004Co-Authors: Osmond J Dcruz, Barbara Waurzyniak, Fatih M. UckunAbstract:WHI-07 [5-bromo-6-methoxy-5,6-dihydro-3′-azidothymidine-5′-(p-bromophenyl)-methoxy alaninyl phosphate] is a novel dual-function aryl phosphate derivative of zidovudine with potent anti-human immunodeficiency virus (HIV) and spermicidal activities. WHI-07 was active against the feline immunodeficiency virus (FIV). This study evaluated whether topical application of WHI-07 as a single agent and in combination with an organometallic vanadium complex, Vanadocene dithiocarbamate (VDDTC), via a nontoxic gel microemulsion can block vaginal as well as rectal transmission of feline AIDS (FAIDS) by chronically FIV-infected feline T cells in the natural host model. Genital transmission of FIV was monitored in recipient cats by the appearance of viral antibodies to FIV Gag proteins and by virus isolation of blood leukocytes as measured by FIV reverse transcriptase activity and FIV-specific PCR. Microbicidal activity was considered effective when the treated cats did not show evidence of FIV infection for up to 18 weeks postchallenge. An aggregate analysis of 46 specific-pathogen-free cats revealed that a single dose of the infected cell inoculum efficiently transmitted FIV infection when delivered into the vagina (100%) or rectum (66%). Pretreatment of the vagina or rectum with 2% WHI-07 alone or in combination with 0.25% VDDTC significantly (P = 0.004) protected cats from genital transmission by the highly infectious inoculum (7 million FIVBangston-infected feline T cells). Collectively, using the vaginal and rectal transmucosal model for FAIDS, our studies demonstrated that WHI-07 either alone or in combination with a Vanadocene has clinical potential for the development of a dual-function anti-HIV microbicide for sexually active women.
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subchronic 13 week toxicity studies of intravaginal administration of spermicidal Vanadocene acetylacetonato monotriflate in mice
Toxicology, 2002Co-Authors: Osmond J Dcruz, Barbara Waurzyniak, Fatih M. UckunAbstract:Bis-cyclopentadienyl complexes of vanadium(IV) or Vanadocenes are rapid and potent inhibitors of human sperm motility with potential as a new class of contraceptive agents. In this study, groups of 10 B6C3F1 and 20 CD-1 female mice were exposed intravaginally to a gel-microemulsion containing 0, 0.06, 0.12, or 0.25% of a representative Vanadocene, Vanadocene acetylacetonato monotriflate (VDACAC), five days per week for 13 consecutive weeks. The doses of VDACAC used were nearly 300- to 1250-fold higher than its in vitro spermicidal EC50 value. After 13 weeks of intravaginal treatment, B6C3F1 mice were evaluated for survival, body weight gain, absolute and relative organ weights, and systemic toxicity. Blood was analyzed for hematological and clinical chemistry profiles. Microscopic examination was performed on hematoxylin- and eosin-stained tissue sections from each study animal. Vanadium content in tissues was determined by atomic absorption spectroscopy. Gel-microemulsion (placebo) control and VDACAC dosed female CD-1 mice were mated with untreated males in order to evaluate if VDACAC has any adverse effects on the reproductive outcome. There were no treatment-related mortalities in either study. Mean body weight gain during the dosing period was not reduced by VDACAC treatment. Hemograms or clinical chemistry profiles did not reveal any toxicologically significant changes attributed to VDACAC treatment. No clinically significant dose-dependent changes in absolute and relative organ weights were noted in VDACAC dose groups. Extensive histopathological examination of tissues revealed no treatment-related abnormalities in any of the three VDACAC dose groups. Vanadium was not incorporated in mouse tissues at levels above 1 μg/g. Repeated intravaginal exposure of CD-1 mice to increasing concentrations of VDACAC for 13 weeks had no adverse effect on their subsequent reproductive capability (100% fertile), neonatal survival (>96%) or pup development. Collectively, these findings demonstrate that repetitive intravaginal administration of VDACAC to yield effective spermicidal concentrations (<0.1%) in the vagina was not associated with systemic toxicity and did not adversely affect the reproductive performance in mice. The spermicidal Vanadocene-chelated complex, VDACAC, may be useful as a safe vaginal contraceptive.
Jaromír Vinklárek - One of the best experts on this subject based on the ideXlab platform.
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Vanadocene complexes bearing n n chelating ligands synthesis structures and in vitro cytotoxic studies on the a549 lung adenocarcinoma cell line
Journal of Inorganic Biochemistry, 2019Co-Authors: Jan Honzíček, Ivana Císařová, Martina řezacova, Aneta Machálková, Lucie Melounková, Radim Havelek, Eva Peterova, Jaromír VinklárekAbstract:Abstract Ten new Vanadocene complexes bearing N,N′-chelating ligands were prepared, characterized, and their cytotoxicity toward a panel of cancer cells was measured. Structures of four Vanadocene compounds were determined by single crystal X-ray diffraction analysis. Complexes containing 1,2-bis(phenylimino)acenaphthene (bian) and 1,2-bis(4-methoxyphenylimino)acenaphthene (4-MeO-bian) exhibit higher cytotoxicity than those with dipyrido[3,2-a:2′,3′-c]phenazine (dppz) and (E)-N-((pyridin-2-yl)methylene)benzenamine (pyma). In light of the finding, cytotoxic mechanisms of two highly effective complexes [(η5-C5H4Me)2V(bian)][OTf]2 (3b) and [(η5-C5H4Me)2V(4-MeO-bian)][OTf]2 (4b) against human A549 lung adenocarcinoma cells were investigated by following membrane leakage of intracellular lactate dehydrogenase, Trypan Blue staining and activation of tumor protein p53 (p53). Evaluated complexes have a potent dose-dependent antiproliferative activity, causing cell cycle redistribution by the increased accumulation of cells in the G2 and S phase. In accord with the observed cell cycle deceleration, cyclin-dependent kinase inhibitor-interacting protein 1 (p21WAF1/Cip1), extracellular signal–regulated kinases 1 and 2 (ERK1/2), Checkpoint kinase 1 (Chk1), Checkpoint kinase 2 (Chk2) and their phosphorylated forms Chk1 at serine 345 and Chk2 at threonine 68 increased. In the cells exposed to complexes, dose- and time-dependent apoptotic process is initiated by the activation of the initiator caspase 8, followed by activation of effector caspase 3/7 and phosphatidylserine externalization. Moreover, because of treatment, A549 cells activate prosurvival mitogen-activated protein kinases (MAPK) signaling and up-regulate antiapoptotic protein B-cell lymphoma (Bcl-2), thereby promoting evasion of cell death. Both complexes exhibited considerably higher cytotoxic effect than the reference anticancer drug cis-platin and the cytotoxicity was more pronounced at higher treatment time.
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Synthesis, characterization and cytotoxic activity of Vanadocene dithiocarbamate complexes
Inorganica Chimica Acta, 2019Co-Authors: Ivana Císařová, Jaromír Vinklárek, Aneta Machálková, Lucie Melounková, Jan HonzíčekAbstract:Abstract This study describes synthesis of water-soluble Vanadocene and 1,1′-dimethylVanadocene compounds bearing dithiocarbamate ligands. All prepared compounds were characterized by analytical and spectroscopic methods. The structure of [(η5-C5H4Me)2V{S2CN(CH2)4O}]Cl was determined by single-crystal X-ray diffraction analysis. The cytotoxicity of the synthesized compounds was investigated on human leukemia cells MOLT-4. The derivatives bearing cyclic dithiocarbamates show considerably stronger activity than reported for cisplatin.
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Hydrolysis of Vanadocene dichloride: A revisit
Inorganica Chimica Acta, 2016Co-Authors: Jan Honzíček, Zdeňka Růžičková, Jaromír VinklárekAbstract:Abstract A key hydrolysis product of Vanadocene dichloride was isolated and structurally characterized. The oligomeric character of the species precludes its detection by classical EPR spectroscopic tools. A detailed study of the with high purity reagents disproves appearance of Cp2V(OH)2, which was postulated previously based on mechanistic approach.
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synthesis characterization and cytotoxic effect of Vanadocene complexes bearing substituted 2 2 bipyridines and 4 5 diazafluoren 9 one
Inorganica Chimica Acta, 2015Co-Authors: Lucie Šebestová, Jan Honzíček, Jaromír Vinklárek, Zdeňka Růžičková, Martina řezacovaAbstract:Abstract This study describes the synthesis of Vanadocene compounds [Cp′ 2 V(L)][OTf] 2 , where Cp′ is substituted cyclopentadienyl ring and L is N , N -chelating ligand. All prepared compounds were characterized by analytical and spectroscopic methods. The structures of [( η 5 -C 5 H 4 Me) 2 V(bpy)][OTf] 2 , [( η 5 -C 5 H 4 i Pr) 2 V(bpy)][OTf] 2 ·CH 2 Cl 2 , [Cp 2 V(4,4′-Me 2 -bpy)][OTf] 2 , [Cp 2 V{4,4′-(MeO) 2 -bpy}][OTf] 2 ·MeOH and [( η 5 -C 5 H 4 Me) 2 V(dafone)][OTf] 2 were further confirmed by the X-ray diffraction analysis. The cytotoxicity study, performed on human leukemia cells MOLT-4 and HL-60, demonstrates that the activity of the Vanadocene complexes strongly depends on the nature of the coordinated chelating ligand. The high cytotoxicity was observed for the complex bearing 2,2′-bipyridine, [( η 5 -C 5 H 4 Me) 2 V(bpy)][OTf] 2 , that shows IC 50 values close to the data observed for cisplatin.
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Bioinorganic chemistry of Vanadocene dichloride
Inorganica Chimica Acta, 2015Co-Authors: Jan Honzíček, Jaromír VinklárekAbstract:This review article summarizes the development in bioinorganic chemistry of Vanadocene dichloride and its derivatives. It is focused mainly on studies related with biological activity appearing in past four decades, after the antitumor activity of bent metallocenes was discovered by Petra Köpf-Maier and Hartmut Köpf. The first part deals with the unique hydrolytic chemistry of Vanadocene dichloride and the reactivity with biologically relevant molecules, necessary for understanding of its antitumor effect on the molecular level. The second part summarizes the results of in vitro and in vivo biological assays. It covers not only the experiments related with antitumor activity but also a series of studies focused on the spermicidal properties with unique mechanism of action. A special attention is given to structure-activity studies on modified Vanadocene compounds.
Jan Honzíček - One of the best experts on this subject based on the ideXlab platform.
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Vanadocene complexes bearing n n chelating ligands synthesis structures and in vitro cytotoxic studies on the a549 lung adenocarcinoma cell line
Journal of Inorganic Biochemistry, 2019Co-Authors: Jan Honzíček, Ivana Císařová, Martina řezacova, Aneta Machálková, Lucie Melounková, Radim Havelek, Eva Peterova, Jaromír VinklárekAbstract:Abstract Ten new Vanadocene complexes bearing N,N′-chelating ligands were prepared, characterized, and their cytotoxicity toward a panel of cancer cells was measured. Structures of four Vanadocene compounds were determined by single crystal X-ray diffraction analysis. Complexes containing 1,2-bis(phenylimino)acenaphthene (bian) and 1,2-bis(4-methoxyphenylimino)acenaphthene (4-MeO-bian) exhibit higher cytotoxicity than those with dipyrido[3,2-a:2′,3′-c]phenazine (dppz) and (E)-N-((pyridin-2-yl)methylene)benzenamine (pyma). In light of the finding, cytotoxic mechanisms of two highly effective complexes [(η5-C5H4Me)2V(bian)][OTf]2 (3b) and [(η5-C5H4Me)2V(4-MeO-bian)][OTf]2 (4b) against human A549 lung adenocarcinoma cells were investigated by following membrane leakage of intracellular lactate dehydrogenase, Trypan Blue staining and activation of tumor protein p53 (p53). Evaluated complexes have a potent dose-dependent antiproliferative activity, causing cell cycle redistribution by the increased accumulation of cells in the G2 and S phase. In accord with the observed cell cycle deceleration, cyclin-dependent kinase inhibitor-interacting protein 1 (p21WAF1/Cip1), extracellular signal–regulated kinases 1 and 2 (ERK1/2), Checkpoint kinase 1 (Chk1), Checkpoint kinase 2 (Chk2) and their phosphorylated forms Chk1 at serine 345 and Chk2 at threonine 68 increased. In the cells exposed to complexes, dose- and time-dependent apoptotic process is initiated by the activation of the initiator caspase 8, followed by activation of effector caspase 3/7 and phosphatidylserine externalization. Moreover, because of treatment, A549 cells activate prosurvival mitogen-activated protein kinases (MAPK) signaling and up-regulate antiapoptotic protein B-cell lymphoma (Bcl-2), thereby promoting evasion of cell death. Both complexes exhibited considerably higher cytotoxic effect than the reference anticancer drug cis-platin and the cytotoxicity was more pronounced at higher treatment time.
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Synthesis, characterization and cytotoxic activity of Vanadocene dithiocarbamate complexes
Inorganica Chimica Acta, 2019Co-Authors: Ivana Císařová, Jaromír Vinklárek, Aneta Machálková, Lucie Melounková, Jan HonzíčekAbstract:Abstract This study describes synthesis of water-soluble Vanadocene and 1,1′-dimethylVanadocene compounds bearing dithiocarbamate ligands. All prepared compounds were characterized by analytical and spectroscopic methods. The structure of [(η5-C5H4Me)2V{S2CN(CH2)4O}]Cl was determined by single-crystal X-ray diffraction analysis. The cytotoxicity of the synthesized compounds was investigated on human leukemia cells MOLT-4. The derivatives bearing cyclic dithiocarbamates show considerably stronger activity than reported for cisplatin.
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Hydrolysis of Vanadocene dichloride: A revisit
Inorganica Chimica Acta, 2016Co-Authors: Jan Honzíček, Zdeňka Růžičková, Jaromír VinklárekAbstract:Abstract A key hydrolysis product of Vanadocene dichloride was isolated and structurally characterized. The oligomeric character of the species precludes its detection by classical EPR spectroscopic tools. A detailed study of the with high purity reagents disproves appearance of Cp2V(OH)2, which was postulated previously based on mechanistic approach.
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synthesis characterization and cytotoxic effect of Vanadocene complexes bearing substituted 2 2 bipyridines and 4 5 diazafluoren 9 one
Inorganica Chimica Acta, 2015Co-Authors: Lucie Šebestová, Jan Honzíček, Jaromír Vinklárek, Zdeňka Růžičková, Martina řezacovaAbstract:Abstract This study describes the synthesis of Vanadocene compounds [Cp′ 2 V(L)][OTf] 2 , where Cp′ is substituted cyclopentadienyl ring and L is N , N -chelating ligand. All prepared compounds were characterized by analytical and spectroscopic methods. The structures of [( η 5 -C 5 H 4 Me) 2 V(bpy)][OTf] 2 , [( η 5 -C 5 H 4 i Pr) 2 V(bpy)][OTf] 2 ·CH 2 Cl 2 , [Cp 2 V(4,4′-Me 2 -bpy)][OTf] 2 , [Cp 2 V{4,4′-(MeO) 2 -bpy}][OTf] 2 ·MeOH and [( η 5 -C 5 H 4 Me) 2 V(dafone)][OTf] 2 were further confirmed by the X-ray diffraction analysis. The cytotoxicity study, performed on human leukemia cells MOLT-4 and HL-60, demonstrates that the activity of the Vanadocene complexes strongly depends on the nature of the coordinated chelating ligand. The high cytotoxicity was observed for the complex bearing 2,2′-bipyridine, [( η 5 -C 5 H 4 Me) 2 V(bpy)][OTf] 2 , that shows IC 50 values close to the data observed for cisplatin.
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Bioinorganic chemistry of Vanadocene dichloride
Inorganica Chimica Acta, 2015Co-Authors: Jan Honzíček, Jaromír VinklárekAbstract:This review article summarizes the development in bioinorganic chemistry of Vanadocene dichloride and its derivatives. It is focused mainly on studies related with biological activity appearing in past four decades, after the antitumor activity of bent metallocenes was discovered by Petra Köpf-Maier and Hartmut Köpf. The first part deals with the unique hydrolytic chemistry of Vanadocene dichloride and the reactivity with biologically relevant molecules, necessary for understanding of its antitumor effect on the molecular level. The second part summarizes the results of in vitro and in vivo biological assays. It covers not only the experiments related with antitumor activity but also a series of studies focused on the spermicidal properties with unique mechanism of action. A special attention is given to structure-activity studies on modified Vanadocene compounds.
Osmond J. D'cruz - One of the best experts on this subject based on the ideXlab platform.
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Original research article Vaginal contraceptive activity of a chelated Vanadocene
2005Co-Authors: Osmond J. D'cruz, Fatih M. UckunAbstract:Bis(cyclopentadienyl) complexes of vanadium (IV) or Vanadocenes are rapid and potent inhibitors of human sperm motility with potential as a new class of contraceptive agents. This study sought to determine the vaginal contraceptive activity of Vanadocene dithiocarbamate (VDDTC), a stable Vanadocene (IV)-chelated complex, using the standard rabbit model as well as the domestic pig as a physiologically relevant animal model for contraception. In experiment I, ovulating New Zealand White does in subgroups of eight were artificially inseminated (AI) with semen mixed with VDDTC (0.01–1 mM) or vehicle. In experiment II, ovulating does in subgroups of 18 were AI at 5 and 60 min after intravaginal application of a gel with and without 0.1% VDDTC or 2% nonoxynol-9 (N-9) (Gynol II, Ortho Pharmaceutical, Raritan, NJ), and allowed to complete term pregnancy. In experiment III, seven sexually mature Duroc gilts in standing estrus were AI with and without intravaginal application of 0.1% VDDTC gel microemulsion. Exposure of rabbit semen to VDDTC at the time of artificial insemination resulted in a dose-dependent reduction in fertility. Exposure of semen to 1 mM VDDTC led to complete inhibition of fertility as assessed by the number of embryos (control 49/94 vs. VDDTC-treated 0/117, p b .0001) or the percent embryos (52% vs. 0%, respectively) based on number of embryos to corpora lutea. Intravaginal administration of 0.1% VDDTC gel microemulsion or Gynol II prior to artificial insemination significantly inhibited term pregnancy rates (88% and 62% inhibition, respectively) when compared to control gel alone. Vanadocene dithiocarbamate gel microemulsion provided 80% inhibition of fertility even when insemination was delayed until 60 min after intravaginal application of VDDTC gel microemulsion. Rabbits that delivered litters despite intravaginal exposure of semen to VDDTC via gel microemulsion had healthy offsprings with no apparent perinatal repercussions. In domestic pigs, intravaginal applications of 0.1% VDDTC gel microemulsion prior to artificial insemination led to complete inhibition of fertility as assessed by the number of embryos (control 29/52 vs. VDDTC-treated 0/44, p b .0001) or the percent embryos (56% vs. 0%, respectively) based on the number of embryos to corpora lutea. These results suggest that VDDTC is a potent contraceptive agent in vivo. Intravaginal use of VDDTC via a gel microemulsion has clinical potential as a safe alternative to currently used detergent-type contraceptives.
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Vaginal contraceptive activity of a chelated Vanadocene.
Contraception, 2005Co-Authors: Osmond J. D'cruz, Fatih M. UckunAbstract:Abstract Bis(cyclopentadienyl) complexes of vanadium (IV) or Vanadocenes are rapid and potent inhibitors of human sperm motility with potential as a new class of contraceptive agents. This study sought to determine the vaginal contraceptive activity of Vanadocene dithiocarbamate (VDDTC), a stable Vanadocene (IV)-chelated complex, using the standard rabbit model as well as the domestic pig as a physiologically relevant animal model for contraception. In experiment I, ovulating New Zealand White does in subgroups of eight were artificially inseminated (AI) with semen mixed with VDDTC (0.01���1 mM) or vehicle. In experiment II, ovulating does in subgroups of 18 were AI at 5 and 60 min after intravaginal application of a gel with and without 0.1% VDDTC or 2% nonoxynol-9 (N-9) (Gynol II, Ortho Pharmaceutical, Raritan, NJ), and allowed to complete term pregnancy. In experiment III, seven sexually mature Duroc gilts in standing estrus were AI with and without intravaginal application of 0.1% VDDTC gel microemulsion. Exposure of rabbit semen to VDDTC at the time of artificial insemination resulted in a dose-dependent reduction in fertility. Exposure of semen to 1 mM VDDTC led to complete inhibition of fertility as assessed by the number of embryos (control 49/94 vs. VDDTC-treated 0/117, p
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Subchronic (13-week) toxicity studies of intravaginal administration of spermicidal Vanadocene dithiocarbamate in mice.
Contraception, 2001Co-Authors: Osmond J. D'cruz, Barbara Waurzyniak, Fatih M. UckunAbstract:Abstract Spermicidal organometallic complexes of vanadium(IV) with bis (cyclopentadienyl) rings or Vanadocenes are a new class of experimental contraceptive agents. In a systematic search for Vanadocenes with selective spermicidal activity, we identified Vanadocene dithiocarbamate (VDDTC) as the most potent and stable spermicidal compound. In this study, groups of 10 B 6 C 3 F 1 and 20 female CD-1 mice were exposed intravaginally to a gel-microemulsion containing 0, 0.06, 0.12, and 0.25% VDDTC 5 days per week for 13 consecutive weeks. The doses of VDDTC used were nearly 1250- to 5000-fold higher than its in vitro spermicidal EC 50 value. After 13 weeks of intravaginal treatment, B 6 C 3 F 1 mice were evaluated for survival, body weight gain, absolute and relative organ weights, and systemic toxicity. Blood was analyzed for hematologic and clinical chemistry parameters. Microscopic examination was performed on hematoxylin and eosin-stained tissue sections from each study animal. Vanadium content in tissues was determined by atomic absorption spectroscopy. Placebo control and VDDTC-dosed female CD-1 mice were mated with untreated males to evaluate whether VDDTC has any deleterious effects on the reproductive performance. There were no treatment-related effects on survival and mean body weight and mean body weight gain during the dosing period. The blood chemistry or hemogram profiles did not reveal any toxicologically significant changes that could be attributed to VDDTC treatment. No clinically significant changes in absolute and relative organ weights were noted in VDDTC dose groups. Extensive histopathological examination of tissues revealed no treatment-related abnormalities in any of the three VDDTC dose groups. The vanadium content of all mouse tissue analyzed was 90%), or pup development. Collectively, these findings demonstrate that repetitive intravaginal administration of VDDTC to yield effective spermicidal concentrations (
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Original research article Subchronic (13-week) toxicity studies of intravaginal administration of spermicidal Vanadocene dithiocarbamate in mice
2001Co-Authors: Osmond J. D'cruz, Barbara Waurzyniak, Fatih M. UckunAbstract:Spermicidal organometallic complexes of vanadium(IV) with bis(cyclopentadienyl) rings or Vanadocenes are a new class of experimental contraceptive agents. In a systematic search for Vanadocenes with selective spermicidal activity, we identified Vanadocene dithiocarbamate (VDDTC) as the most potent and stable spermicidal compound. In this study, groups of 10 B6C3F1 and 20 female CD-1 mice were exposed intravaginally to a gel-microemulsion containing 0, 0.06, 0.12, and 0.25% VDDTC 5 days per week for 13 consecutive weeks. The doses of VDDTC used were nearly 1250- to 5000-fold higher than its in vitro spermicidal EC50 value. After 13 weeks of intravaginal treatment, B6C3F1 mice were evaluated for survival, body weight gain, absolute and relative organ weights, and systemic toxicity. Blood was analyzed for hematologic and clinical chemistry parameters. Microscopic examination was performed on hematoxylin and eosin-stained tissue sections from each study animal. Vanadium content in tissues was determined by atomic absorption spectroscopy. Placebo control and VDDTC-dosed female CD-1 mice were mated with untreated males to evaluate whether VDDTC has any deleterious effects on the reproductive performance. There were no treatment-related effects on survival and mean body weight and mean body weight gain during the dosing period. The blood chemistry or hemogram profiles did not reveal any toxicologically significant changes that could be attributed to VDDTC treatment. No clinically significant changes in absolute and relative organ weights were noted in VDDTC dose groups. Extensive histopathological examination of tissues revealed no treatment-related abnormalities in any of the three VDDTC dose groups. The vanadium content of all mouse tissue analyzed was 1 g/g. Repeated intravaginal exposure of CD-1 mice to increasing concentrations of VDDTC for 13 weeks had no adverse effect on their subsequent reproductive capability (100% fertile), neonatal survival (90%), or pup development. Collectively, these findings demonstrate that repetitive intravaginal administration of VDDTC to yield effective spermicidal concentrations (0.1%) in the vagina was not associated with systemic toxicity and did not adversely affect the reproductive performance in mice. VDDTC may have clinical utility as an active ingredient of non-detergent type, safe, vaginal spermicidal contraceptives. © 2001 Elsevier Science Inc. All rights reserved.
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Vanadocene-mediated in vivo male germ cell apoptosis.
Toxicology and applied pharmacology, 2000Co-Authors: Osmond J. D'cruz, Fatih M. UckunAbstract:Vanadocenes are potent apoptosis-inducing cytotoxic agents against human testicular cancer cells in vitro. The present study investigated the ability of four Vanadocenes-Vanadocene diazide (VDA), Vanadocene dicyanate (VDCN), Vanadocene dioxycyanate (VDOCN), and Vanadocene monochloro oxycyanate (VDCO)-to induce male germ cell apoptosis in vivo in mouse testes by repetitive intratesticular injection of Vanadocenes (7.5 mg/kg/testis) for 28 days. Germ cell loss in vivo was measured by epididymal sperm count, testes weights, and histologic evaluation of the testes. Repetitive intratesticular injection of Vanadocenes led to decreased sperm counts and reduced testicular weights. Histopathological examination revealed seminiferous tubular atrophy, inhibition of spermatogenesis, and the preferential loss of maturing and elongated spermatids. In situ evaluation by the terminal deoxynucleotidyl transferase-mediated FITC-deoxyuridine triphosphate nick-end labeling (TUNEL) of seminiferous tubule cross sections and laser confocal microscopy showed characteristic apoptotic cells identified primarily as pachytene spermatocytes delineating the periphery of the seminiferous tubules. The ability of Vanadocenes to induce germ cell apoptosis in vivo may have potential utility in the treatment of testicular seminomas in humans.
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Vanadocene complexes bearing n n chelating ligands synthesis structures and in vitro cytotoxic studies on the a549 lung adenocarcinoma cell line
Journal of Inorganic Biochemistry, 2019Co-Authors: Jan Honzíček, Ivana Císařová, Martina řezacova, Aneta Machálková, Lucie Melounková, Radim Havelek, Eva Peterova, Jaromír VinklárekAbstract:Abstract Ten new Vanadocene complexes bearing N,N′-chelating ligands were prepared, characterized, and their cytotoxicity toward a panel of cancer cells was measured. Structures of four Vanadocene compounds were determined by single crystal X-ray diffraction analysis. Complexes containing 1,2-bis(phenylimino)acenaphthene (bian) and 1,2-bis(4-methoxyphenylimino)acenaphthene (4-MeO-bian) exhibit higher cytotoxicity than those with dipyrido[3,2-a:2′,3′-c]phenazine (dppz) and (E)-N-((pyridin-2-yl)methylene)benzenamine (pyma). In light of the finding, cytotoxic mechanisms of two highly effective complexes [(η5-C5H4Me)2V(bian)][OTf]2 (3b) and [(η5-C5H4Me)2V(4-MeO-bian)][OTf]2 (4b) against human A549 lung adenocarcinoma cells were investigated by following membrane leakage of intracellular lactate dehydrogenase, Trypan Blue staining and activation of tumor protein p53 (p53). Evaluated complexes have a potent dose-dependent antiproliferative activity, causing cell cycle redistribution by the increased accumulation of cells in the G2 and S phase. In accord with the observed cell cycle deceleration, cyclin-dependent kinase inhibitor-interacting protein 1 (p21WAF1/Cip1), extracellular signal–regulated kinases 1 and 2 (ERK1/2), Checkpoint kinase 1 (Chk1), Checkpoint kinase 2 (Chk2) and their phosphorylated forms Chk1 at serine 345 and Chk2 at threonine 68 increased. In the cells exposed to complexes, dose- and time-dependent apoptotic process is initiated by the activation of the initiator caspase 8, followed by activation of effector caspase 3/7 and phosphatidylserine externalization. Moreover, because of treatment, A549 cells activate prosurvival mitogen-activated protein kinases (MAPK) signaling and up-regulate antiapoptotic protein B-cell lymphoma (Bcl-2), thereby promoting evasion of cell death. Both complexes exhibited considerably higher cytotoxic effect than the reference anticancer drug cis-platin and the cytotoxicity was more pronounced at higher treatment time.
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Synthesis, characterization and cytotoxic activity of Vanadocene dithiocarbamate complexes
Inorganica Chimica Acta, 2019Co-Authors: Ivana Císařová, Jaromír Vinklárek, Aneta Machálková, Lucie Melounková, Jan HonzíčekAbstract:Abstract This study describes synthesis of water-soluble Vanadocene and 1,1′-dimethylVanadocene compounds bearing dithiocarbamate ligands. All prepared compounds were characterized by analytical and spectroscopic methods. The structure of [(η5-C5H4Me)2V{S2CN(CH2)4O}]Cl was determined by single-crystal X-ray diffraction analysis. The cytotoxicity of the synthesized compounds was investigated on human leukemia cells MOLT-4. The derivatives bearing cyclic dithiocarbamates show considerably stronger activity than reported for cisplatin.
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Synthesis, characterization and cytotoxic effect of ring-substituted and ansa -bridged Vanadocene complexes
Inorganica Chimica Acta, 2011Co-Authors: Jan Honzíček, Jaromír Vinklárek, Ivana Císařová, Zdeňka Padělková, Iva Klepalová, Pavel Siman, Martina ŘezáčováAbstract:Abstract The cytotoxic effect of Vanadocene dichloride (Cp2VCl2, 1) and its ring-substituted, (η5-C5H4Me)2VCl2 (2), (η5-C5Me5)2VCl2 (3), (η5-C5H4R)2VCl2 (4: R = MeOCH2CH2–, 5: R = 2-MeOC6H4CH2–, 6: R = 4-MeOC6H4CH2–) and ansa-bridged analogs Me2C(η5-C5H4)2VCl2 (7) and Me4C2(η5-C5H4)2VCl2 (8) was investigated. Synthesis of two new methoxy-functionalized compounds (4 and 5) is described. They were characterized by spectroscopic methods and X-ray diffraction analysis. The cytotoxicity studies were performed with leukemic cells MOLT-4.
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Synthesis and structural investigation of Vanadocene(IV) complexes of non-linear pseudohalides
Inorganica Chimica Acta, 2009Co-Authors: Jan Honzíček, Jaromír Vinklárek, Ivana Císařová, Milan ErbenAbstract:Abstract Two series of Vanadocene complexes of the type Cp 2 ′ VX 2 (Cp′ = η 5 -C 5 H 5 , η 5 -C 5 H 4 Me; X = dicyanamide, tricyanomethanide, dicyanonitrosomethanide) were prepared by the reaction of appropriate Vanadocene dichloride complex with alkali salt of non-linear pseudohalide. The bonding mode of pseudohalide ligands was determined by spectroscopic measurements and X-ray diffraction analyses.
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Vanadocene(IV) dicyanide complexes: the evidence super-hyperfine coupling for compounds with 13CN ligands.
Magnetic resonance in chemistry : MRC, 2007Co-Authors: Jan Honzíček, Jaromír Vinklárek, Zdeněk Černošek, Ivana CísařováAbstract:An EPR study of the Vanadocene complexes (C5H5)2V(CN)2 and (CH3C5H4)2V(CN)2 was carried out. Such compounds show strong super-hyperfine coupling (|aiso(13C)|∼1.27 mT) when 13C labeled cyanide is used for their preparation. Super-hyperfine splitting was observed in the isotropic spectra of solution samples as well as in the anisotropic spectra of frozen solutions. Such studies were supplemented with structural characterization of the parent compounds. Molecular structure of the complex (CH3C5H4)2V(CN)2 was determined by single-crystal X-ray diffraction analysis. Both compounds were characterized by infrared and Raman spectroscopy. Copyright © 2007 John Wiley & Sons, Ltd.
