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1.
Wilderness Environ Med ; 31(2): 157-164, 2020 Jun.
Article in English | MEDLINE | ID: mdl-32205041

ABSTRACT

INTRODUCTION: A history of preexisting hypertension is common in people participating in mountain activities; however, the relationship between blood pressure (BP), preexisting hypertension, and acute mountain sickness (AMS) is not well studied. We sought to determine these relationships among trekkers in the Everest region of Nepal. METHODS: This was a prospective observational cohort study of a convenience sample of adult, nonpregnant volunteers trekking in the Everest Base Camp region in Nepal. We recorded Lake Louise Scores for AMS and measured BP at 2860 m, 3400 m, and 4300 m. The primary outcome was AMS. RESULTS: A total of 672 trekkers (including 60 with history of preexisting hypertension) were enrolled at 2860 m. We retained 529 at 3400 m and 363 at 4300 m. At 3400 m, 11% of participants had AMS, and 13% had AMS at 4300 m. We found no relationship between AMS and measured BP values (P>0.05), nor was there any relation of BP to AMS severity as measured by higher Lake Louise Scores (P>0.05). Preexisting hypertension (odds ratio [OR] 0.16; 95% CI 0.025-0.57), male sex (OR 0.59; 95% CI 0.37-0.96), and increased SpO2 (OR 0.93; 95% CI 0.87-0.98) were associated with reduced rates of AMS in multivariate analyses adjusting for known risk factors for AMS. CONCLUSIONS: AMS is common in trekkers in Nepal, even at 3400 m. There is no relationship between measured BP and AMS. However, a medical history of hypertension may be associated with a lower risk of AMS. More work is needed to confirm this novel finding.


Subject(s)
Altitude Sickness/epidemiology , Altitude , Hypertension/complications , Mountaineering , Acute Disease/epidemiology , Adult , Aged , Altitude Sickness/etiology , Altitude Sickness/physiopathology , Blood Pressure , Female , Humans , Male , Middle Aged , Nepal/epidemiology , Prevalence , Prospective Studies , Risk Factors
2.
Cancer Res ; 77(22): 6282-6298, 2017 11 15.
Article in English | MEDLINE | ID: mdl-28978635

ABSTRACT

Androgen receptor (AR) mediates the growth of prostate cancer throughout its course of development, including in abnormal splice variants (AR-SV)-driven advanced stage castration-resistant disease. AR stabilization by androgens makes it distinct from other steroid receptors, which are typically ubiquitinated and degraded by proteasomes after ligand binding. Thus, targeting AR in advanced prostate cancer requires the development of agents that can sustainably degrade variant isoforms for effective therapy. Here we report the discovery and characterization of potent selective AR degraders (SARD) that markedly reduce the activity of wild-type and splice variant isoforms of AR at submicromolar doses. Three SARDs (UT-69, UT-155, and (R)-UT-155) bind the amino-terminal transcriptional activation domain AF-1, which has not been targeted for degradation previously, with two of these SARD (UT-69 and UT-155) also binding the carboxy-terminal ligand binding domain. Despite different mechanisms of action, all three SARDs degraded wild-type AR and inhibited AR function, exhibiting greater inhibitory potency than the approved AR antagonists. Collectively, our results introduce a new candidate class of next-generation therapeutics to manage advanced prostate cancer. Cancer Res; 77(22); 6282-98. ©2017 AACR.


Subject(s)
Androgen Receptor Antagonists/pharmacology , Gene Expression Regulation, Neoplastic/drug effects , Prostatic Neoplasms, Castration-Resistant/drug therapy , Receptors, Androgen/genetics , Alternative Splicing , Androgen Receptor Antagonists/chemistry , Anilides/chemistry , Anilides/pharmacology , Animals , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Proliferation/genetics , Gene Expression Profiling/methods , Humans , Indoles/chemistry , Indoles/pharmacology , Male , Mice, Inbred NOD , Mice, Knockout , Mice, SCID , Molecular Structure , Prostatic Neoplasms, Castration-Resistant/genetics , Prostatic Neoplasms, Castration-Resistant/metabolism , Receptors, Androgen/metabolism , Xenograft Model Antitumor Assays
3.
Expert Opin Ther Pat ; 22(5): 541-65, 2012 May.
Article in English | MEDLINE | ID: mdl-22583332

ABSTRACT

INTRODUCTION: Androgen receptor (AR) antagonists are predominantly used as chemical castration to treat prostate cancer (i.e., in conjunction with androgen deprivation therapy (ADT)). Unfortunately, castration-resistant prostate cancer (CRPC) typically develops that is refractory to targeted therapy. Insights into CRPC biology have led to the emergence of a promising clinical candidate MDV3100 (1) and a resurgence in this field. A pipeline of preclinical competitive (C-terminally directed) antagonists was discovered using a variety of innovative screening paradigms. Some inhibit nuclear translocation, selectively downregulate or degrade AR (SARD), antagonize wild-type and escape mutant AR (pan-antagonists) and/or antagonize AR target organs in vivo. Separately, the N-terminal domain has emerged as a promising novel target for noncompetitive antagonists. AREAS COVERED: AR antagonists whose patents published between 2008 and 2011 are reviewed. Antagonists are organized based on the screening paradigm reported as discussed above. EXPERT OPINION: Novel mechanisms provide a more informed basis for selecting a competitive antagonist; however, high potency and favorable in vivo properties remain paramount. Noncompetitive antagonists have theoretical advantages suggestive of improved clinical efficacy, but no clinical proof of concept as of yet.


Subject(s)
Androgen Receptor Antagonists/pharmacology , Antineoplastic Agents, Hormonal/pharmacology , Prostatic Neoplasms/drug therapy , Receptors, Androgen/drug effects , Androgen Receptor Antagonists/chemistry , Animals , Antineoplastic Agents, Hormonal/chemistry , Drug Design , Drug Resistance, Neoplasm , Humans , Legislation, Drug , Male , Molecular Structure , Mutation , Patents as Topic , Prostatic Neoplasms/genetics , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology , Protein Transport , Receptors, Androgen/genetics , Receptors, Androgen/metabolism , Structure-Activity Relationship
4.
Pharm Res ; 29(8): 2079-91, 2012 Aug.
Article in English | MEDLINE | ID: mdl-22451249

ABSTRACT

PURPOSE: Overexpression of the androgen receptor (AR) and anti-apoptotic genes including X-linked inhibitor of apoptosis protein (XIAP) provide tumors with a proliferative advantage. Therefore, our objective was to determine whether novel antiandrogen (CBDIV17) and XIAP inhibitor based combination therapy can treat advanced prostate cancer. METHODS: CBDIV17 and embelin-6g were synthesized and their effect on cell proliferation, apoptosis, cell cycle and AR and XIAP gene silencing determined. RESULTS: CBDIV17 was more potent than bicalutamide and inhibited proliferation of C4-2 and LNCaP cells, IC(50) for CBDIV17 was ≈ 12 µM and ≈ 21 µM in LNCaP and C4-2 cells, respectively, whereas bicalutamide had IC(50) of ≈ 46 µM in LNCaP cells and minimal effect in C4-2 cells. CBDIV17 induced apoptosis more effectively compared to bicalutamide and significantly inhibited DNA replication. Combination of CBDIV17 and embelin resulted in supra-additive antiproliferative and apoptotic effects. Embelin downregulated AR expression and decreased androgen-mediated AR phosphorylation at Ser(81). These hydrophobic drugs were solubilized using micelles prepared with polyethylene glycol-b-poly (carbonate-co-lactide) (PEG-b-p(CB-co-LA)) copolymer. Combination therapy inhibited prostate tumor growth more effectively compared to control or monotherapy in vivo. CONCLUSIONS: Our results demonstrated that CBDIV17 in combination with embelin can potentially treat advanced prostate cancer.


Subject(s)
Androgen Antagonists/therapeutic use , Anilides/therapeutic use , Antineoplastic Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Benzoquinones/therapeutic use , Hydroxybutyrates/therapeutic use , Prostatic Neoplasms/drug therapy , X-Linked Inhibitor of Apoptosis Protein/antagonists & inhibitors , Androgen Antagonists/administration & dosage , Androgen Antagonists/pharmacology , Anilides/administration & dosage , Anilides/pharmacology , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacology , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Apoptosis/drug effects , Benzoquinones/administration & dosage , Benzoquinones/pharmacology , Cell Cycle/drug effects , Cell Line, Tumor , Gene Expression Regulation, Neoplastic/drug effects , Humans , Hydroxybutyrates/administration & dosage , Hydroxybutyrates/pharmacology , Male , Mice , Micelles , Nitriles/pharmacology , Prostate/drug effects , Prostate/metabolism , Prostate/pathology , Prostatic Neoplasms/genetics , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology , Receptors, Androgen/genetics , Receptors, Androgen/metabolism , Tosyl Compounds/pharmacology , X-Linked Inhibitor of Apoptosis Protein/genetics , X-Linked Inhibitor of Apoptosis Protein/metabolism
5.
J Med Chem ; 54(11): 3973-6, 2011 Jun 09.
Article in English | MEDLINE | ID: mdl-21506597

ABSTRACT

Several new androgen receptor antagonists were synthesized and found to have varying activities across typically anti-androgen resistant mutants (Thr877 → Ala and Trp741 → Leu) and markedly improved potency over previously reported pan-antagonists. X-ray crystallography of a new anti-androgen in an androgen receptor mutant (Thr877 → Ala) shows that the receptor can accommodate the added bulk presented by phenyl to naphthyl substitution, casting doubt on previous reports of predicted binding orientation and the causes of antagonism in bulky-B-ring antagonists.


Subject(s)
Androgen Antagonists/chemistry , Androgen Receptor Antagonists/chemistry , Androgens/chemistry , Drug Resistance, Neoplasm/genetics , Prostatic Neoplasms/genetics , Receptors, Androgen/metabolism , Androgen Antagonists/chemical synthesis , Androgen Antagonists/metabolism , Androgen Receptor Antagonists/chemical synthesis , Androgen Receptor Antagonists/metabolism , Androgen Receptor Antagonists/pharmacology , Androgens/pharmacology , Crystallography, X-Ray , Drug Design , Humans , Male , Molecular Structure , Molecular Targeted Therapy , Prostatic Neoplasms/drug therapy , Protein Binding , Receptors, Androgen/chemistry , Structure-Activity Relationship
6.
Drug Metab Dispos ; 39(4): 636-43, 2011 Apr.
Article in English | MEDLINE | ID: mdl-21233217

ABSTRACT

3-(1H-Indol-2-yl)phenyl)(3,4,5-trimethoxyphenyl)methanone (I-387) is a novel indole compound with antitubulin action and potent antitumor activity in various preclinical models. I-387 avoids drug resistance mediated by P-glycoprotein and showed less neurotoxicity than vinca alkaloids during in vivo studies. We examined the pharmacokinetics and metabolism of I-387 in mice as a component of our preclinical development of this compound and continued interest in structure-activity relationships for antitubulin agents. After a 1 mg/kg intravenous dose, noncompartmental pharmacokinetic analysis in plasma showed that clearance (CL), volume of distribution at steady state (Vd(ss)), and terminal half-life (t(1/2)) of I-387 were 27 ml per min/kg, 5.3 l/kg, and 7 h, respectively. In the in vitro metabolic stability study, half-lives of I-387 were between 10 and 54 min by mouse, rat, dog, monkey, and human liver microsomes in the presence of NADPH, demonstrating interspecies variability. I-387 was most stable in rat liver microsomes and degraded quickly in monkey liver microsomes. Liquid chromatography-tandem mass spectrometry was used to identify phase I metabolites. Hydroxylation, reduction of a ketone group, and O-demethylation were the major metabolites formed by the liver microsomes of the five species. The carbonyl group of I-387 was reduced and identified as the most labile site in human liver microsomes. The results of these drug metabolism and pharmacokinetic studies provide the foundation for future structural modification of this pharmacophore to improve stability of drugs with potent anticancer effects in cancer patients.


Subject(s)
Antimitotic Agents/metabolism , Benzophenones/metabolism , Indoles/metabolism , Microsomes, Liver/metabolism , NADP/metabolism , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Animals , Antimitotic Agents/blood , Antimitotic Agents/chemical synthesis , Antimitotic Agents/pharmacology , Benzophenones/blood , Benzophenones/chemical synthesis , Benzophenones/pharmacology , Biotransformation , Dogs , Drug Stability , Half-Life , Haplorhini , Humans , Hydroxylation , Indoles/blood , Indoles/chemical synthesis , Indoles/pharmacology , Injections, Intravenous , Metabolic Detoxication, Phase I , Metabolic Detoxication, Phase II , Mice , Microsomes, Liver/drug effects , Rats , Species Specificity , Structure-Activity Relationship
7.
Cancer Chemother Pharmacol ; 67(2): 293-304, 2011 Feb.
Article in English | MEDLINE | ID: mdl-20383708

ABSTRACT

PURPOSE: Microtubules are one of the most useful subcellular targets in chemotherapy. We identified a novel indole, (3-(1H-indol-2-yl)phenyl)(1H-indol-2-yl)methanone (15), that inhibits tubulin action and exhibits potent antitumor activity in various preclinical models. METHODS: In vitro cancer cell growth inhibition was measured by SRB or MTT assay in human cancer cell lines. Apoptosis induced by 15 was examined in LNCaP and PC-3 cells. Effects of 15 on cell cycle distribution and tubulin were investigated via in vitro models. In vivo toxicity and xenograft efficacy studies were conducted in mice. RESULTS: Indole 15 inhibited the in vitro growth of a number of human cancer cell lines, including drug-resistant cell lines that over-express P-glycoprotein, multidrug resistance-associated proteins, and breast cancer resistance protein with IC(50) values in the range of 34-162 nM. Nanomolar concentrations of the compound caused down-regulation of bcl-2, induced PARP cleavage, and induced apoptosis in both LNCaP and PC-3 prostate cancer cells, as confirmed by anti-histone ELISA and DNA laddering. In vitro studies revealed that the compound inhibited polymerization of purified tubulin and induced a strong and concentration-dependent G(2)M arrest in PC-3 cells. In vivo studies in immunodeficient mice bearing PC-3 tumor xenografts showed that the compound effectively inhibited tumor growth. CONCLUSIONS: The potent in vitro and in vivo antitumor activities of this novel indole suggest that drugs with this novel chemical scaffold might be developed for treatment of drug-resistant prostate cancer.


Subject(s)
Indoles/pharmacology , Indoles/therapeutic use , Microtubules/drug effects , Prostatic Neoplasms/drug therapy , Tubulin Modulators/pharmacology , Tubulin Modulators/therapeutic use , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , ATP Binding Cassette Transporter, Subfamily G, Member 2 , ATP-Binding Cassette Transporters/metabolism , Animals , Apoptosis/drug effects , Binding Sites , Binding, Competitive , Cell Cycle/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Humans , Indoles/chemistry , Indoles/metabolism , Indoles/toxicity , Inhibitory Concentration 50 , Male , Maximum Tolerated Dose , Mice , Mice, Inbred ICR , Mice, Nude , Molecular Structure , Multidrug Resistance-Associated Proteins/metabolism , Neoplasm Proteins/metabolism , Podophyllotoxin/metabolism , Prostatic Neoplasms/pathology , Survival Rate , Tubulin/metabolism , Tubulin Modulators/chemistry , Tubulin Modulators/metabolism , Tubulin Modulators/toxicity , Vinblastine/metabolism , Xenograft Model Antitumor Assays
8.
Mol Cancer Ther ; 9(11): 2859-68, 2010 Nov.
Article in English | MEDLINE | ID: mdl-20829196

ABSTRACT

(3-(1H-indol-2-yl)phenyl)(3,4,5-trimethoxyphenyl)methanone (I-387) is a novel synthetic compound that inhibits tubulin action and exhibits potent antitumor activity in various preclinical models. I-387 inhibited the in vitro growth of several human cancer cell lines with IC50 values in the range of 15 to 39 nmol/L. Nanomolar concentrations of the compound induced apoptosis and caused phosphorylation of the antiapoptotic protein Bcl-2. I-387 induced a strong and concentration-dependent G2-M arrest in PC-3 cells by constitutive activation of Cdc2/cyclin B1 complex and destabilized polymerization of purified tubulin in vitro by binding to the colchicine-binding site. In vivo, I-387 treatment effectively inhibited tumor growth in mice bearing PC-3 tumor xenografts. In vitro studies of nerve growth factor-dependent neurite outgrowth in PC12 pheochromocytoma cells and in vivo studies of mouse behavior showed that I-387 was less neurotoxic than vinblastine and vincristine, tubulin destabilizers with known neurotoxicity. Interestingly, multidrug-resistant cell lines that overexpressed P-glycoprotein (P-gp), multidrug resistance-associated proteins, and breast cancer resistance protein were rendered resistant to docetaxel, vinblastine, SN-38, and doxorubicin, but not to I-387. I-387 dosed at 10 mg/kg was equally effective with 76% tumor growth inhibition in xenograft models using MES-SA uterine sarcoma cells and MES-SA/DX5 cells overexpressing P-gp. In contrast, docetaxel and vinblastine were not effective in MES-SA/DX5 xenograft models. The potent in vitro and in vivo antitumor activity of I-387 suggests that it may represent a new antimitotic agent for management of various malignancies, particularly for patients with drug-resistant cancer.


Subject(s)
Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacology , Benzophenones/pharmacology , Indoles/pharmacology , Neurons/drug effects , Neurons/pathology , Animals , Antimitotic Agents/adverse effects , Antimitotic Agents/pharmacology , Antimitotic Agents/therapeutic use , Antineoplastic Agents/therapeutic use , Apoptosis/drug effects , Benzophenones/adverse effects , Benzophenones/therapeutic use , Cells, Cultured , HT29 Cells , Humans , Indoles/adverse effects , Indoles/therapeutic use , K562 Cells , Male , Mice , Mice, Inbred ICR , Mice, Nude , Neurotoxicity Syndromes/epidemiology , Neurotoxicity Syndromes/pathology , PC12 Cells , Rats , Xenograft Model Antitumor Assays
9.
J Pharmacol Exp Ther ; 334(2): 439-48, 2010 Aug.
Article in English | MEDLINE | ID: mdl-20444881

ABSTRACT

Women experience a decline in estrogen and androgen levels after natural or surgically induced menopause, effects that are associated with a loss of sexual desire and bone mineral density. Studies in our laboratories have shown the beneficial effects of selective androgen receptor modulators (SARMs) in the treatment of osteoporosis and muscle wasting in animal models. A series of S-3-(phenoxy)-2-hydroxy-2-methyl-N-(4-cyano-3-trifluoromethyl-phenyl)-propionamide analogs was synthesized to evaluate the effects of B-ring substitutions on in vitro and in vivo pharmacologic activity, especially female sexual motivation. The androgen receptor (AR) relative binding affinities ranged from 0.1 to 26.5% (relative to dihydrotestosterone) and demonstrated a range of agonist activity at 100 nM. In vivo pharmacologic activity was first assessed by using male rats. Structural modifications to the B-ring significantly affected the selectivity of the SARMs, demonstrating that single-atom substitutions can dramatically and unexpectedly influence activity in androgenic (i.e., prostate) and anabolic (i.e., muscle) tissues. (S)-N-(4-cyano-3-trifluoromethyl-phenyl)-3-(3-fluoro,4-chlorophenoxy)-2-hydroxy-2-methyl-propanamide (S-23) displayed full agonist activity in androgenic and anabolic tissues; however, the remaining SARMs were more prostate-sparing, selectively maintaining the size of the levator ani muscle in castrated rats. The partner-preference paradigm was used to evaluate the effects of SARMs on female sexual motivation. With the exception of two four-halo substituted analogs, the SARMs increased sexual motivation in ovariectomized rats, with potency and efficacy comparable with testosterone propionate. These results indicate that the AR is important in regulating female libido given the nonaromatizable nature of SARMs and it could be a superior alternative to steroidal testosterone preparations in the treatment of hypoactive sexual desire disorder.


Subject(s)
Androgens , Anilides/pharmacology , Receptors, Androgen/physiology , Sexual Behavior, Animal/drug effects , Anilides/chemistry , Animals , Binding, Competitive , Cell Line , Female , Follicle Stimulating Hormone/blood , Humans , Luteinizing Hormone/blood , Male , Orchiectomy , Organ Size , Ovariectomy , Prostate/anatomy & histology , Prostate/drug effects , Radioligand Assay , Rats , Rats, Sprague-Dawley , Sex Factors , Stereoisomerism , Structure-Activity Relationship , Transcriptional Activation , Uterus/anatomy & histology , Uterus/drug effects
10.
Acta Crystallogr Sect E Struct Rep Online ; 66(Pt 2): m148, 2010 Jan 13.
Article in English | MEDLINE | ID: mdl-21579627

ABSTRACT

The structure of the title compound, [Cr(C(10)H(12)O(2))(CO)(3)], is presented. The distorted piano-stool geometry features an off-center Cr(CO)(3) fragment which reduces contact with the dioxolane ring. The dioxolane ring, in twisted conformation, is syn-oriented towards the Cr(CO)(3) moiety.

11.
Pharm Res ; 26(9): 2081-92, 2009 Sep.
Article in English | MEDLINE | ID: mdl-19415464

ABSTRACT

PURPOSE: To examine the effect of bicalutamide and embelin on the growth of prostate cancer cells in vitro and in vivo METHODS: Cell viability was determined by MTT assay. Micelles were fabricated with polyethylene glycol-b-polylactic acid (PEG-PLA) copolymer and characterized in terms of particle size, micellar solubilization and drug loading, followed by evaluation in nude mice bearing LNCaP xenografts. RESULTS: Embelin induced caspase 3 and 9 activation in LNCaP and C4-2 cells by decreasing XIAP expression and was more potent than bicalutamide in killing prostate tumor cells irrespective of their androgen status. As analyzed by isobologram analysis the combination of bicalutamide and embelin was synergistic for C4-2 but additive and slightly antagonistic for LNCaP cells. Micellar formulation resulted in at least 60-fold increase in the aqueous solubility of bicalutamide and embelin. Tumor growth was effectively regressed upon treatment with bicalutamide, but the extent of tumor regression was significantly higher when bicalutamide was formulated in micelles. However, tumor response to bicalutamide stopped after prolonged treatment and began to grow. Sequential treatment with XIAP inhibitor embelin resulted in regression of these hormone refractory tumors. CONCLUSION: Combined treatment with bicalutamide and embelin may be an effective strategy for treating hormone refractory prostate cancer.


Subject(s)
Anilides/therapeutic use , Antineoplastic Agents/therapeutic use , Benzoquinones/therapeutic use , Micelles , Nitriles/therapeutic use , Prostatic Neoplasms/drug therapy , Tosyl Compounds/therapeutic use , Anilides/administration & dosage , Anilides/pharmacology , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Base Sequence , Benzoquinones/administration & dosage , Benzoquinones/pharmacology , Cell Line, Tumor , DNA Primers , Humans , Male , Mice , Mice, Nude , Nitriles/administration & dosage , Nitriles/pharmacology , Tosyl Compounds/administration & dosage , Tosyl Compounds/pharmacology , Transplantation, Heterologous
12.
J Phys Chem A ; 113(12): 2666-76, 2009 Mar 26.
Article in English | MEDLINE | ID: mdl-19231828

ABSTRACT

We review recent studies of processes relevant to photoinduced linkage isomerization of organometallic systems with the goal of preparing organometallics with an efficient and ultrafast photochromic response. The organometallic system thus corresponds to two linkage isomers with different electronic environments that are responsible for different optical properties. Much of this work has focused on examining processes following irradiation of cyclopentadienyl manganese tricarbonyl derivatives (compounds 3-21) including solvent coordination, thermal relaxation, solvent displacement by tethered functional groups (chelation), dissociation of tethered functional groups, and linkage isomerization. A new platform is investigated for obtaining a photochromic response in new experiments with arene chromium dicarbonyl complexes. A photochromic response is observed for arene chromium dicarbonyl complexes with tethered pyridine and olefin functional groups based on light-driven linkage isomerization on the nanosecond time scale. Irradiation at 532 nm of 23 ([Cr{eta(6)-C(6)H(5)CH(2-Py-kappaN)CH(2)CH=CH(2)}(CO)(2)]) (Py = pyridine) results in the isomerization to 22 ([Cr{eta(6)-C(6)H(5)CH(2-Py)CH(2)-eta(2)-CH=CH(2)}(CO)(2)]), and 355 nm irradiation isomerizes 22 to 23. The ultrafast linkage isomerization has been investigated at room temperature in n-heptane solution on the picosecond to microsecond time scale with UV- or visible-pump and IR-probe transient absorption spectroscopy by comparing the dynamics with model compounds containing only a tethered pyridine. Irradiation of 24 ([Cr{eta(6)-C(6)H(5)(CH(2))(3)(2-Py)}(CO)(3)]) and 25 ([Cr{eta(6)-C(6)H(5)(CH(2))(2)(2-Py)}(CO)(3)]) at 289 nm induces CO loss to immediately yield a Cr-heptane solvent coordinated intermediate of the unsaturated Cr fragment, which then converts to the kappaN(1)-pyridine chelate within 200 and 100 ns, respectively. Irradiation of 26 ([Cr{eta(6)-C(6)H(5)CH(2)(2-Py)}(CO)(3)]) also induces CO loss to immediately yield three species: the Cr-heptane solvent coordinated intermediate, a kappaN(1)-Py nitrogen chelate, and an agostic eta(2)-chelate in which the pyridine is coordinated to the metal center via a C-H agostic bond as opposed to the nitrogen lone pair. Both the transient Cr-heptane coordinated intermediate and the agostic pyridine chelate convert to the stable kappaN(1)-pyridine chelate within 50 ns. Similar reaction dynamics and transient species are observed for the chelate 33 ([Cr{eta(6)-C(6)H(5)CH(2)(2-Py)-kappaN}(CO)(2)]) where a Cr-Py bond, not a Cr-CO bond, initially cleaves.

13.
J Phys Chem A ; 111(30): 6933-7, 2007 Aug 02.
Article in English | MEDLINE | ID: mdl-17628047

ABSTRACT

The chelation dynamics of three new [Cr{eta6-C6H5C(O)R}(CO)3] complexes, 1 [R = CH2(SCH3)], 2 [R = CH(SCH3)2], and 3 [R = C(SCH3)3], has been investigated on the picosecond to millisecond time scales by UV pump/IR probe transient absorption spectroscopy following photodissociation of CO in room temperature n-heptane, tetrahydrofuran (THF), and acetonitrile. In n-heptane, UV irradiation of 1, 2, or 3 dissociates CO to initially yield a Cr-S chelate (in which the pendant sulfide moiety is coordinated to the metal center) and a transient Cr-heptane solvate in approximately 1:2, 1:2, and 2:1 ratios, respectively. The Cr-heptane solvate is unstable and converts to the Cr-S chelate within 30 ns in each case. Irradiation of 2 or 3 in THF yields both the Cr-S chelate and Cr-THF solvate in approximately 1:3 and 1:1 ratios, respectively. The Cr-THF solvate converts to the Cr-S chelate on the second or longer time scale. All three complexes appear to yield the Cr-NCCH3 solvate exclusively within 50 ps following irradiation in acetonitrile. The solvent effect on chelation is in striking contrast to that previously reported for the analogous RCpMn(CO)3 derivatives, 4-6. In acetonitrile, only chelation is observed for the Mn series and only solvent coordination is observed for the Cr series, but in heptane both chelation and solvent coordination are observed in both series.

14.
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