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Role of Metabolism in Chemically Induced Nephrotoxicity
Published in Robin S. Goldstein, Mechanisms of Injury in Renal Disease and Toxicity, 2020
The other proposed mechanism of CPH-induced nephrotoxicity, that of oxidative stress, involves the two other functional groups (Figure 4, pathways a and c). Various workers proposed that the thiophene ring may be metabolized by renal cytochrome P-450 to a reactive epoxide that can interact with cellular nucleophiles such as GSH (Tune, 1986). The GSH depletion thereby makes proximal tubular cells susceptible to oxidative injury (Kuo et al., 1983). Conflicting results, however, in studies with P-450 inhibitors and the inability to isolate a CPH-GSH conjugate from CPH-treated animals have raised questions about the quantitative importance of this metabolic pathway in CPH bioactivation. In studies with 4-(2-thienyl)butyric acid, which is an analog of the thiophene group of CPH, Lash and colleagues found that this agent produces potent cytotoxicity in freshly isolated proximal tubular cells from rat kidney (Lash, L.H., Tokarz, J.J., and Woods, E.B., unpublished data). Cytotoxicity was associated with GSH oxidation and lipid peroxidation. This suggests that although the characteristic nephrotoxicity produced by CPH and other cephalosporins can be accounted for by the β-lactam ring, the thiophene ring may contribute significantly to the overall cytotoxic response produced by CPH.
Chemoenzymatic Approaches towards (S)-Duloxetine
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Danish Shahzad, Muhammad Faisal, Aamer Saeed
Wada et al. reported the screening and gene cloning of the NADPH-dependent ethyl 3-oxo-3-(thiophen-2-yl)propanoate-reducing enzyme (Wada et al., 2004). Exiguobacterium sp. F42 is screened as a producer of this enzyme, which is able to perform reduction of ethyl 3-oxo-3-(2-thienyl)propanoate (KEES) 34 to ethyl (S)-3-hydroxy-3-(2-thienyl)propanoate (HEES) 35, which is a key precursor for the total synthesis of (S)-duloxetine 1, with tremendous enatioselectivity and high yield (Scheme 5.13). Furthermore, for its high level of production, the responsible enzyme (KEES-reductase) is partially decontaminated, and the gene encoding KEES reductase is cloned and sequenced through an inverse polymerase chain reaction (PCR) methodology. The gene is then expressed in Escherichia coli (abbreviated as E. coli), and the gene product is decontaminated to homogeneity from the recombinant E. coli through simpler methods than from the original host (Wada et al., 2004). This KEES-reductase enzyme is the first example of an enzyme active for reduction of thiophene-entity-containing esters. Role of recombinant Exiguobacterium sp. F42 in (S)-duloxetine synthesis.
The Application of Fragment-based Approaches to the Discovery of Drugs for Neglected Tropical Diseases
Published in Venkatesan Jayaprakash, Daniele Castagnolo, Yusuf Özkay, Medicinal Chemistry of Neglected and Tropical Diseases, 2019
Christina Spry, Anthony G. Coyne
Noble et al. (2016) screened the Novartis library of 1408 fragments in pools of eight against RdRp using X-ray crystallography. DENV-3 RdRp crystals were soaked with a total of 176 fragment pools, with each fragment tested at a concentration of 625 μM. This led to the identification of a single fragment hit (compound 35) that was subsequently shown by SPR to bind DENV-3 and DENV-4 RdRp with KD values of 210 and 610 μM, respectively (LE = 0.28 and 0.24, respectively). The structure of DENV-3 RdRp, like that of other polymerases, resembles a right hand with subdomains that mimic the fingers, palm and thumb. The fragment hit was observed to bind in a novel allosteric pocket of apo DENV-3 RdRp, between the thumb and palm subdomains and the priming loop that regulates binding of the RNA template and polymerization. Importantly, binding at this site was also shown to translate into an inhibitory effect on enzyme activity, with an IC50 value of 730 μM determined against DENV-4 RdRp in a de novo initiation/elongation assay. Replacement of the terminal phenyl moiety of fragment 35 with a thiophene produced a fragment (36, Figure 6b) with two-to-seven-fold improved affinity and the same binding mode. Guided by X-ray crystallography, this thiophene fragment was subsequently elaborated using a fragment growing strategy (Yokokawa et al. 2016).
Synthesis of novel, DNA binding heterocyclic dehydroabietylamine derivatives as potential antiproliferative and apoptosis-inducing agents
Published in Drug Delivery, 2020
Fengyi Zhao, Xu Sun, Wen Lu, Li Xu, Jiuzhou Shi, Shilong Yang, Mengyi Zhou, Fan Su, Feng Lin, Fuliang Cao
Thiophene derivatives are ubiquitous in nature and can be found in the structure of various drugs and medicines, produced by combustion of fossil fuels or by the general cooking process (Dyreborg et al., 1996; Dalvie et al., 2002; Medower et al., 2008). Thiophenes bear extensive pharmacological properties such as analgesic, antipyretic, and antiandrogenic activities (Hana et al., 2008; Huang et al., 2012; Iványi et al., 2012). Furthermore, a great number of thiophene derivatives are used as antitumor agents (Lesyk et al., 2006; Kulandasamy et al., 2009; Khalil et al., 2010; Ye et al., 2010). For instance, OSI-930 is an investigational anticancer agent which contains thiophene moiety (Petti et al., 2005; Garton et al., 2006). Ghorab et al. (2016) reported a series of thiophene derivatives with high anti-MCF-7 (breast adenocarcinoma) cancer activity (half maximal inhibitory concentration [IC50] = 33.1–66.3 μM). Mohareb and Al-Omran (2012) have studied three thiophene derivatives exhibited much higher inhibitory effects toward three tumor cell lines, MCF-7, NCI-H460 (non-small cell lung cancer), and SF-268 (CNS cancer) with GC50 value in the range of 0.01–16.2 μM than the reference drug, doxorubicin (DOX).
Design, synthesis and antitumor activity of 5-trifluoromethylpyrimidine derivatives as EGFR inhibitors
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Yaqing Zuo, Rongrong Li, Yan Zhang, Guochen Bao, Yi Le, Longjia Yan
Thiophene derivatives exist broad activities in the field of pharmaceutical researches especially in anti-microbial, anti-tumour, anti-oxidation, and anti-inflammatory activity15–17. As shown in Figure 1, Olmutinib, a kind of thienopyrimidine compound was an important EGFR inhibitor in market to treat nonsmall-cell lung cancer (NSCLC)18. Moreover, OSI-930 in Figure 1 was a good anticancer reagent as kinase inhibitor in clinical trials for multiple tumors19. In addition, more and more thiophene derivatives were successfully developed as antitumor reagents20–23.
Anti-Angiogenic Effect of Cantharellus cibarius Extracts, its Correlation with Lipoxygenase Inhibition, and Role of the Bioactives Therein
Published in Nutrition and Cancer, 2022
Sandesh J. Marathe, Wahiba Hamzi, Abdulla M. Bashein, Jan Deska, Tuulikki Seppänen-Laakso, Rekha S. Singhal, Salem Shamekh
The ethanol extracts showed presence of thiophene, 2-decyl (compound 14, Table 3). Novel thiophene inhibitors have been reported for their LOX inhibitory activity (48). Thiophene derivatives have also been reported as potent dual inhibitors of LOX and cyclooxygenase as well as anticancer agents from their in vitro and in vivo studies (49). Moreover, thiophene carboxamides have also been reported for their VEGF receptor-2 inhibitory activity (50), pointing at its anti-angiogenic potential.