Application of Dithiocarbamates as Potential New Antitrypanosomatids-Drugs: Approach Chemistry, Functional and Biological

Oliveira, Johny Wysllas de Freitas; Rocha, Hugo Alexandre Oliveira; Medeiros, Wendy Marina Toscano Queiroz de; Silva, Marcelo S.

doi:10.3390/molecules24152806

Cited by 45 publications

(26 citation statements)

References 90 publications

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“…Disulfiram, also known as Antabuse, is an FDA-approved drug that has been used to treat alcohol dependence for several decades, with well-established pharmacokinetic properties, safety and tolerance (30). Disulfiram has shown varying activity against parasites, with an even greater antiparasitic potency observed when complexed to zinc (ZnDTC) (41). However, these observations were based mainly on in vitro studies, and the underlying mechanisms that explain the enhanced potency remain poorly understood.…”

Section: Discussionmentioning

confidence: 99%

COP9 signalosome is an essential and druggable parasite target that regulates protein degradation

Ghosh

Farr

Singh

et al. 2020

Preprint

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Understanding how the protozoan protein degradation pathway is regulated could uncover new parasite biology for drug discovery. We found the COP9 signalosome (CSN) conserved in multiple pathogens such as Leishmania, Trypanosoma, Toxoplasma, and used the severe diarrhea-causing Entamoeba histolytica to study its function in medically significant protozoa. We show that CSN is an essential upstream regulator of parasite protein degradation. Genetic disruption of E. histolytica CSN by two distinct approaches inhibited cell proliferation and viability. Both CSN5 knockdown and dominant negative mutation trapped cullin in a neddylated state, disrupting UPS activity and protein degradation. In addition, zinc ditiocarb (ZnDTC), a main metabolite of the inexpensive FDA-approved alcohol-abuse drug disulfiram, was active against parasites acting in a COP9-dependent manner. ZnDTC, given as disulfiram-zinc, had oral efficacy in clearing parasites in vivo. Our findings provide insights into the regulation of parasite protein degradation, and supports the significant therapeutic potential of COP9 inhibition.Summary sentenceParasite-encoded COP9 signalosome is an essential upstream regulator of ubiquitin-proteasome mediated protein degradation, and shows significant potential as a therapeutic target.

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Section: Discussionmentioning

confidence: 99%

COP9 signalosome is an essential and druggable parasite target that regulates protein degradation

Ghosh

Farr

Singh

et al. 2020

Preprint

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“…Inspired by the intramolecular HAT reactions to functionalize the unactivated C(sp 3 )-H bonds, Alexanian's group reported an intramolecular C(sp 3 )-H dithiocarbamylation of valine in which the dithiocarbamate worked as the transfer group (Scheme 52) [106]. Importantly, the dithiocarbamate group is an attractive pharmacophore with versatile pharmacological activities, such as antimicrobial, antifungal, antiviral, and antiparasitic activities, as well as a multifunctional precursor for allylation, deuteration, azidation, and thiolation [107,108].…”

Section: C(sp 3 )-S Formationmentioning

confidence: 99%

Recent Advances in Rapid Synthesis of Non-proteinogenic Amino Acids from Proteinogenic Amino Acids Derivatives via Direct Photo-Mediated C–H Functionalization

Yuan

Liu

et al. 2020

Molecules

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Non-proteinogenic amino acids have attracted tremendous interest for their essential applications in the realm of biology and chemistry. Recently, rising C–H functionalization has been considered an alternative powerful method for the direct synthesis of non-proteinogenic amino acids. Meanwhile, photochemistry has become popular for its predominant advantages of mild conditions and conservation of energy. Therefore, C–H functionalization and photochemistry have been merged to synthesize diverse non-proteinogenic amino acids in a mild and environmentally friendly way. In this review, the recent developments in the photo-mediated C–H functionalization of proteinogenic amino acids derivatives for the rapid synthesis of versatile non-proteinogenic amino acids are presented. Moreover, postulated mechanisms are also described wherever needed.

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“…In the search for metal complexes with a novel pharmacological basis, metal complexes of dithiocarbamates are being explored. Their anti-cancer activities are attributed to their ability to form a complex with tumour cellular copper to inhibit the proteasome and, in turn, to initiate tumor cell-specific apoptosis [ 11 , 12 ]. Different metal complexes of dithiocarbamates with promising anticancer activities have been studied [ 13 , 14 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

Synthesis, Crystal Structures and Anticancer Studies of Morpholinyldithiocarbamato Cu(II) and Zn(II) Complexes

et al. 2020

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Cu(II) and Zn(II) morpholinyldithiocarbamato complexes, formulated as [Cu(MphDTC)2] and [Zn(μ-MphDTC)2(MphDTC)2], where MphDTC is morpholinyldithiocarbamate were synthesized and characterized by elemental analysis, spectroscopic techniques and single-crystal X-ray crystallography. The molecular structure of the Cu(II) complex revealed a mononuclear compound in which the Cu(II) ion was bonded to two morpholinyl dithiocarbamate ligands to form a four-coordinate distorted square planar geometry. The molecular structure of the Zn(II) complex was revealed to be dinuclear, and each metal ion was bonded to two morpholinyl dithiocarbamate bidentate anions, one acting as chelating ligand, the other as a bridge between the two Zn(II) ions. The anticancer activity of the morpholinyldithiocarbamate ligand, Cu(II) and Zn(II) complexes were evaluated against renal (TK10), melanoma (UACC62) and breast (MCF7) cancer cells by a Sulforhodamine B (SRB) assay. Morpholinyldithiocarbamate was more active than the standard drug parthenolide against renal and breast cancer cell lines, and [Zn(μ-MphDTC)2(MphDTC)2] was the most active complex against breast cancer. The copper(II) complex had a comparable activity with the standard against renal and breast cancer cell lines but showed an enhanced potency against melanoma when compared to parthenolide.

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Application of Dithiocarbamates as Potential New Antitrypanosomatids-Drugs: Approach Chemistry, Functional and Biological

Cited by 45 publications

References 90 publications

COP9 signalosome is an essential and druggable parasite target that regulates protein degradation

COP9 signalosome is an essential and druggable parasite target that regulates protein degradation

Recent Advances in Rapid Synthesis of Non-proteinogenic Amino Acids from Proteinogenic Amino Acids Derivatives via Direct Photo-Mediated C–H Functionalization

Synthesis, Crystal Structures and Anticancer Studies of Morpholinyldithiocarbamato Cu(II) and Zn(II) Complexes

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