Chincona alkaloids extracted from the bark stem of Cinchona officinalis have been historically used to treat fever and malaria. More recently, cinchona alkaloid derivatives have been attributed to apoptotic effects in the context of cancer. Similarly, chalcones are plant-derived polyphenolic compounds with known anti-fungal, -microbial, -malarial, and -carcinogenic properties. Here, we reveal cytotoxic and antiproliferative characteristics of synthetic quinine-chalcone hybrids in human cancer cell lines. Two derivatives (AD-12 and AD-13) presented IC₅₀ values below 2 µM in the lung squamous cell carcinoma cell line (EBC-1). Our study shows that AD-12 and AD-13 increased intracellular ROS levels and promoted caspase-3/7, and -8 activity in EBC-1 cells. These apoptotic effects were accompanied by short-term inhibition of P-gp efflux activity, while expression levels of P-gp transporters remained stable. Together, our study illustrates the potential of quinine-chalcone hybrids as novel anticancer drug candidates.

2022-02-24·Journal of Medicinal Chemistry1区 · 医学

Probing the Requirements for Dual Angiotensin-Converting Enzyme C-Domain Selective/Neprilysin Inhibition

1区 · 医学

Article

作者: Sturrock, Edward D. ; Acharya, K. Ravi ; Eyermann, Charles J. ; Basarab, Gregory S. ; Cozier, Gyles E. ; Schwager, Sylva L. ; Arendse, Lauren B. ; Chibale, Kelly

Selective inhibition of the angiotensin-converting enzyme C-domain (cACE) and neprilysin (NEP), leaving the ACE N-domain (nACE) free to degrade bradykinin and other peptides, has the potential to provide the potent antihypertensive and cardioprotective benefits observed for nonselective dual ACE/NEP inhibitors, such as omapatrilat, without the increased risk of adverse effects. We have synthesized three 1-carboxy-3-phenylpropyl dipeptide inhibitors with nanomolar potency based on the previously reported C-domain selective ACE inhibitor lisinopril-tryptophan (LisW) to probe the structural requirements for potent dual cACE/NEP inhibition. Here we report the synthesis, enzyme kinetic data, and high-resolution crystal structures of these inhibitors bound to nACE and cACE, providing valuable insight into the factors driving potency and selectivity. Overall, these results highlight the importance of the interplay between the S₁' and S₂' subsites for ACE domain selectivity, providing guidance for future chemistry efforts toward the development of dual cACE/NEP inhibitors.

2019-05-01·Journal of Affective Disorders2区 · 医学

Screening for perinatal anxiety disorders: Room to grow

2区 · 医学

Article

作者: Ma, Annie ; Thordarson, Dana S ; Corbyn, Bryony ; Fairbrother, Nichole ; Surm, Danika

BACKGROUNDThe anxiety and their related disorders (AD) are the most prevalent of all mental health conditions, disproportionately affecting women. The value of perinatal AD screening is well established but there is very limited evidence to support the applicability of existing anxiety screening instruments. To our knowledge, no previous studies have evaluated an AD screening instrument in a perinatal population using full gold standard methodology.OBJECTIVETo assess the accuracy of the most commonly used and/or recommended screening tools for perinatal AD (i.e., the Edinburgh Postnatal Depression Scale (EPDS) and its anxiety subscale (EPDS-3A), and the Generalized Anxiety Disorder 7 and 2-item Scales (GAD-7 and GAD-2) alongside a clinically derived alternative; the Anxiety Disorder - 13 (AD-13).METHODS310 Canadian women completed mood and anxiety questionnaires at approximately 3-months postpartum. Those scoring at/above cut-off on one or more questionnaire completed a diagnostic interview for depression and all AD (n = 115). The accuracy of each scale was assessed via ROC analyses.RESULTSOnly the AD-13 met the standard of a clinically useful screening measure, with an area under the curve (AUC) above 0.8. This was achieved with and without the inclusion of the related disorders. No other measure demonstrated an AUC above 0.8, either including or excluding the related disorders.CONCLUSIONSNeither the EPDS/EPDS 3-A, nor the GAD-7/GAD-2 can be recommended for widespread use as a perinatal AD screening tool. The high performance of the AD-13 is a good indication that an effective alternative is well within reach.

100 项与 AD-013 相关的药物交易

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