- Calreticulin transacetylase: A novel enzyme-mediated protein acetylation by acetoxy derivatives of 3-alkyl-4-methylcoumarins
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Our earlier investigations culminated in the discovery of a unique membrane-bound enzyme Calreticulin transacetylase (CRTAase) in mammalian cells catalyzing the transfer of acetyl group from polyphenolic acetates (PAs) to certain functional proteins viz. Glutathione S-transferase (GST), NADPH Cytochrome c reductase and Nitric oxide synthase (NOS) resulting in the modulation of their biological activities. In order to develop SAR study, herein, we studied the influence of alkyl group at C-3 position of acetoxy coumarins on the CRTAase activity. The alkylated acetoxy coumarins lead to inhibition of catalytic activity of GST, and ADP induced platelet aggregation by the way of activation of platelet Nitric oxide synthase (NOS). Furthermore, the increase in size of the coumarin C-3 alkyl group was found to decrease the CRTAase activity.
- Jalal, Sarah,Chand, Karam,Kathuria, Abha,Singh, Prabhjot,Priya, Nivedita,Gupta, Bhavna,Raj, Hanumantharao G.,Sharma, Sunil K.
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experimental part
p. 131 - 136
(2012/03/27)
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- Endochin optimization: Structure-activity and structure-property relationship studies of 3-substituted 2-Methyl-4(1 H)-quinolones with antimalarial activity
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Since the 1940s endochin and analogues thereof were known to be causal prophylactic and potent erythrocytic stage agents in avian models. Preliminary screening in a current in vitro assay identified several 4(1H)-quinolones with nanomolar EC50 against erythrocytic stages of multidrug resistant W2 and TM90-C2B isolates of Plasmodium falciparum. Follow-up structure-activity relationship (SAR) studies on 4(1H)-quinolone analogues identified several key features for biological activity. Nevertheless, structure-property relationship (SPR) studies conducted in parallel revealed that 4(1H)-quinolone analogues are limited by poor solubilities and rapid microsomal degradations. To improve the overall efficacy, multiple 4(1H)-quinolone series with varying substituents on the benzenoid quinolone ring and/or the 3-position were synthesized and tested for in vitro antimalarial activity. Several structurally diverse 6-chloro-2-methyl-7-methoxy-4(1H)-quinolones with EC50 in the low nanomolar range against the clinically relevant isolates W2 and TM90-C2B were identified with improved physicochemical properties while maintaining little to no cross-resistance with atovaquone.
- Cross, R. Matthew,Monastyrskyi, Andrii,Mutka, Tina S.,Burrows, Jeremy N.,Kyle, Dennis E.,Manetsch, Roman
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scheme or table
p. 7076 - 7094
(2010/12/25)
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