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Current Medicinal Chemistry 2022Glycosidases, the enzymes responsible for the breakdown of glycoconjugates, including di-, oligo- and polysaccharides, are present across all kingdoms of life. The... (Review)
Review
Glycosidases, the enzymes responsible for the breakdown of glycoconjugates, including di-, oligo- and polysaccharides, are present across all kingdoms of life. The extreme chemical stability of the glycosidic bond combined with the catalytic rates achieved by glycosidases makes them among the most proficient of all enzymes. Given their multitude of roles in vivo, inhibition of these enzymes is highly attractive with potential in the treatment of a vast array of pathologies ranging from lysosomal storage and diabetes to viral infections. Therefore great efforts have been invested in the last three decades to design and synthesize inhibitors of glycosidases leading to a number of drugs currently on the market. Amongst the vast array of structures that have been disclosed, sugars incorporating an amidine moiety have been the focus of many research groups around the world because of their glycosidase transition state-like structure. In this review, we report and discuss the structure, the inhibition profile, and the use of these molecules, including related structural congeners as transition state analogs.
Topics: Amidines; Carbohydrates; Enzyme Inhibitors; Glycoside Hydrolases; Humans; Sugars
PubMed: 34951354
DOI: 10.2174/0929867329666211222164545 -
Pharmacological Research Dec 2004The pharmacokinetics of methadone varies greatly from person to person; so, after the administration of the same dose, considerably different concentrations are obtained... (Review)
Review
The pharmacokinetics of methadone varies greatly from person to person; so, after the administration of the same dose, considerably different concentrations are obtained in different subjects, and the pharmacological effect may be too small in some patients, too strong and prolonged in others. Methadone is mostly metabolised in the liver; the main step consists in the N-demethylation by CYP3A4 to EDDP (2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine), an inactive metabolite. The activity of CYP3A4 varies considerably among individuals, and such variability is the responsible for the large differences in methadone bioavailability. CYP2D6 and probably CYP1A2 are also involved in methadone metabolism. During maintenance treatment with methadone, treatment with other drugs may be necessary due to the frequent comorbidity of drug addicts: psychotropic drugs, antibiotics, anticonvulsants and antiretroviral drugs, which can cause pharmacokinetic interactions. In particular, antiretrovirals, which are CYP3A4 inducers, can decrease the levels of methadone, so causing withdrawal symptoms. Buprenorphine, too, is metabolised by CYP3A4, and may undergo the same interactions as methadone. Since it is impossible to foresee the time-lapse from the administration of another drug to the appearing of withdrawal symptoms, nor how much the daily dose of methadone should be increased in order to prevent them, patients taking combined drug treatments must be carefully monitored. The so far known pharmacokinetic drug-drug interactions of methadone do not have life-threatening consequences for the patients, but they usually cause a decrease of the concentrations and of the effects of the drug, which in turn can cause symptoms of withdrawal and increase the risk of relapse into heroin abuse.
Topics: Animals; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Drug Interactions; Humans; Methadone
PubMed: 15501692
DOI: 10.1016/j.phrs.2004.05.002 -
Chemical Society Reviews Mar 2012Over the last ten years there has been a huge increase in development and applications of organocatalysis in which the catalyst acts as a nucleophile. Amidines and... (Review)
Review
Over the last ten years there has been a huge increase in development and applications of organocatalysis in which the catalyst acts as a nucleophile. Amidines and guanidines are often only thought of as strong organic bases however, a number of small molecules containing basic functional groups have been shown to act as efficient nucleophilic catalysts. This tutorial review highlights the use of amidine, guanidine, and related isothiourea catalysts in organic synthesis, as well as the evidence for the nucleophilic nature of these catalysts. The most common application of these catalysts to date has been in acyl transfer reactions, although the application of these catalysts towards other reactions is an increasing area of interest. In this respect, amidine and guanidine derived catalysts have been shown to be effective in catalysing aldol reactions, Morita-Baylis-Hillman reactions, conjugate additions, carbonylations, methylations, silylations, and brominations.
Topics: Amidines; Catalysis; Guanidines; Molecular Structure; Thiourea
PubMed: 22234578
DOI: 10.1039/c2cs15288f -
Chemical Society Reviews Mar 2012Although several recent reviews dealt with transition metal catalyzed N-arylation of amines (all classes), to date no specific review covering the N-arylation of... (Review)
Review
Although several recent reviews dealt with transition metal catalyzed N-arylation of amines (all classes), to date no specific review covering the N-arylation of amidines and guanidines appeared. Amidines and guanidines are considered as fundamental entities in medicinal chemistry. The appearance of these functional groups in drugs, agrochemicals and natural products justifies a separate description of the current status of the literature on the N-arylation of the amidine and guanidine functionalities. Both acyclic and cyclic derivatives are taken into account. For cyclic amidines/guanidines only systems which possess an exocyclic nitrogen atom are considered. This critical review is largely organized by the type of amidine/guanidine and transition metal used and covers literature up to May 2011 (200 references).
Topics: Amidines; Catalysis; Guanidines; Molecular Structure; Transition Elements
PubMed: 22222274
DOI: 10.1039/c1cs15236j -
The Medical Journal of Australia
Topics: Humans; Methadone; Opioid-Related Disorders; Victoria
PubMed: 2247007
DOI: No ID Found -
International Journal of Cancer Oct 2018Recently, the opioid analgesic d,l-methadone has gained much attention as a potential antineoplastic compound, considerably triggered through lay press and media. In... (Review)
Review
Recently, the opioid analgesic d,l-methadone has gained much attention as a potential antineoplastic compound, considerably triggered through lay press and media. In consequence, physicians and pharmacists are currently confronted with numerous patients willing to use d,l-methadone against their malignancies. Well-performed in vitro and in vivo models have in fact shown pro-apoptotic effects of d,l-methadone or other opioids, but also proliferation-stimulating properties. Moreover, the mechanisms of proposed opioid-stimulated apoptosis are incompletely described or contradicting. Finally, the receptors mostly responsible for induction of apoptosis by d,l-methadone remain unclear as contributions of both µ-opioid receptors, Fas cell death receptors, toll-like receptors, N-Methyl-d-aspartate receptors and opioid growth factor receptors were suggested. Such ambiguity prevents rational application of d,l-methadone or patient stratification to enhance beneficial antineoplastic effects. From a clinical point of view, d,l-methadone and other opioids might in fact prolong survival, but such effects likely originate from their analgesic and neuro-psychotropic properties and, thus, improvements of quality of life. Crucial obstacles to the administration of d,l-methadone are incomplete knowledge about its systemic disposition, highly variable pharmacokinetics, profound drug-drug- or drug-disease interaction and QT-prolongation potential. This article summarizes and rates the pharmacological basis of d,l-methadone as an antineoplastic agent and puts its administration in clinical oncology into perspective. Despite enthralling experimental findings about d,l-methadone-mediated apoptosis in cancerous cells or tissues, clinicians should realize the current lack of evidence for the use of d,l-methadone as an antineoplastic agent. Its administration against cancer pain is, however, tenable, albeit restricted to certain clinical situations.
Topics: Animals; Antineoplastic Agents; Apoptosis; Humans; Methadone; Neoplasms
PubMed: 29516505
DOI: 10.1002/ijc.31356 -
Journal of the American Chemical Society Jul 2023Marine bryozoans continue to provide architecturally fascinating halogenated alkaloids that pose unique challenges for chemical synthesis. The antimalarial alkaloids...
Marine bryozoans continue to provide architecturally fascinating halogenated alkaloids that pose unique challenges for chemical synthesis. The antimalarial alkaloids caulamidines A and B, recently isolated from , contain an intricate bis-amidine core and a chlorine-bearing neopentylic stereocenter. Compared to topologically similar C bis(cyclotryptamine) alkaloids, caulamidines possess an additional carbon atom of unknown biosynthetic origins, which renders their entire skeleton nonsymmetric and nondimeric. Herein, we report the first total synthesis of caulamidine A and confirm its absolute configuration. Key chemical findings include the exploitation of glycol bistriflate to facilitate a rapid, diastereoselective ketone-amidine annulation reaction and a highly diastereoselective hydrogen atom transfer to correctly establish the key chlorine-bearing stereogenic center.
Topics: Stereoisomerism; Chlorine; Ketones; Alkaloids; Methadone
PubMed: 37343162
DOI: 10.1021/jacs.3c04493 -
Canadian Medical Association Journal Oct 1973Methadone and acetylmethadol, although possessing almost all of morphine's pharmacological properties, differ from other morphine-like drugs in their longer action, more... (Comparative Study)
Comparative Study Review
Methadone and acetylmethadol, although possessing almost all of morphine's pharmacological properties, differ from other morphine-like drugs in their longer action, more gradual and less intense withdrawal syndrome, and blockade of euphoric effect of other opiates in addicts. A high percentage of patients maintained on methadone are better able to hold employment or to be otherwise socially productive than when dependent on heroin or morphine.A review of published results and procedures used in methadone maintenance treatment programs for heroin dependence is presented. Former heroin addicts are usually maintained on 80 to 120 mg. (high dose) or 20 to 60 mg. (low dose) oral methadone daily. Some programs are reported to have produced 80% success (patients employed or otherwise socially productive). Selection of patients, availability of allied therapeutic and rehabilitative facilities, strict control of supply, record keeping and periodic evaluation are considered essential.Different criteria ("drug-free" vs. "socially productive") for judging "success" of treatment of heroin-dependent persons by methadone maintenance and administrative problems in large-scale treatment programs constitute the principal aspects of controversy.
Topics: Acetates; Administration, Oral; Adolescent; American Medical Association; Canada; Chemical Phenomena; Chemistry; Drug and Narcotic Control; Female; Heroin Dependence; Humans; Methadone; Pregnancy; Pregnancy Complications; Private Practice; Structure-Activity Relationship; Substance Withdrawal Syndrome; Substance-Related Disorders; United States
PubMed: 4599599
DOI: No ID Found -
The Medical Journal of Australia Oct 1976
Topics: Heroin; Humans; Methadone; Narcotics; Substance-Related Disorders
PubMed: 994962
DOI: No ID Found -
Journal of the American Chemical Society Jan 2014To establish the rates and mechanisms of decomposition of guanidine and amidine derivatives in aqueous solution and the rate enhancements produced by the corresponding...
To establish the rates and mechanisms of decomposition of guanidine and amidine derivatives in aqueous solution and the rate enhancements produced by the corresponding enzymes, we examined their rates of reaction at elevated temperatures and used the Arrhenius equation to extrapolate the results to room temperature. The similar reactivities of methylguanidine and 1,1,3,3-tetramethylguanidine and their negative entropies of activation imply that their decomposition proceeds by hydrolysis rather than elimination. The influence of changing pH on the rate of decomposition is consistent with attack by hydroxide ion on the methylguanidinium ion (k2 = 5 × 10(-6) M(-1) s(-1) at 25 °C) or with the kinetically equivalent attack by water on uncharged methylguanidine. At 25 °C and pH 7, N-methylguanidine is several orders of magnitude more stable than acetamidine, urea, or acetamide. Under the same conditions, the enzymes arginase and agmatinase accelerate substrate hydrolysis 4 × 10(14)-fold and 6 × 10(12)-fold, respectively, by mechanisms that appear to involve metal-mediated water attack. Arginine deiminase accelerates substrate hydrolysis 6 × 10(12)-fold by a mechanism that (in contrast to the mechanisms employed by arginase and agmatinase) is believed to involve attack by an active-site cysteine residue.
Topics: Amidines; Guanidine; Hot Temperature; Hydrogen-Ion Concentration; Hydrolysis; Methylguanidine; Molecular Structure; Thermodynamics; Water
PubMed: 24359273
DOI: 10.1021/ja411927k