McGown Andrew, Nafie Jordan, Otayfah Mohammed, Hassell-Hart Storm, Tizzard Graham J, Coles Simon J, Banks Rebecca, Marsh Graham P, Maple Hannah J, Kostakis George E, Proietti Silvestri Ilaria, Colbon Paul, Spencer John
Department of Chemistry, School of Life Sciences, University of Sussex Falmer BN1 9QJ UK
Sussex Drug Discovery Centre, Department of Chemistry, School of Life Sciences, University of Sussex Falmer BN1 9QJ UK.
RSC Chem Biol. 2023 Aug 8;4(10):716-721. doi: 10.1039/d3cb00082f. eCollection 2023 Oct 4.
Many small molecule bioactive and marketed drugs are chiral. They are often synthesised from commercially available chiral building blocks. However, chirality is sometimes incorrectly assigned by manufacturers with consequences for the end user ranging from: experimental irreproducibility, wasted time on synthesising the wrong product and reanalysis, to the added cost of purchasing the precursor and resynthesis of the correct stereoisomer. Further on, this could lead to loss of reputation, loss of funding, to safety and ethical concerns due to potential administration of the wrong form of a drug. It is our firm belief that more stringent control of chirality be provided by the supplier and, if needed, requested by the end user, to minimise the potential issues mentioned above. Certification of chirality would bring much needed confidence in chemical structure assignment and could be provided by a variety of techniques, from polarimetry, chiral HPLC, using known chiral standards, vibrational circular dichroism, and x-ray crystallography. A few case studies of our brushes with wrong chirality assignment are shown as well as some examples of what we believe to be good practice.
许多具有生物活性且已上市的小分子药物都是手性的。它们通常由市售的手性砌块合成。然而，有时制造商对手性的指定有误，给终端用户带来的后果包括：实验不可重复性、在合成错误产品及重新分析上浪费时间、购买前体以及重新合成正确立体异构体的额外成本。此外，这还可能导致声誉受损、资金损失，以及因可能使用错误形式的药物而引发安全和伦理问题。我们坚信，供应商应提供更严格的手性控制，如有需要，终端用户也可要求，以尽量减少上述潜在问题。手性认证将为化学结构指定带来急需的信心，可通过多种技术提供，包括旋光法、使用已知手性标准品的手性高效液相色谱法、振动圆二色性和X射线晶体学。文中展示了一些我们遇到的手性指定错误的案例研究，以及一些我们认为是良好做法的示例。
