Cryptophycins-1 and 52 (epoxides) were discovered to have in-vitro and in-vivo antitumor activity in the early 1990s. The chlorohydrins of these, Cryptophycins-8 and 55 (also discovered in the early 1990s) were markedly more active, but could not be formulated as stable solutions. With no method to adequately stabilize the chlorohydrins at the time, Cryptophycin-52 (LY 355073) entered clinical trials, producing only marginal antitumor activity. Since that time, glycinate esters of the hydroxyl group of the chlorohydrins have been synthesized and found to provide stability. Three of the most active were compared herein. Cryptophycin-309 (C-309) is a glycinate ester of the chlorohydrin Cryptophycin-296. The glycinate derivative provided both chemical stability and improved aqueous solubility. After the examination of 81 different Cryptophycin analogs in tumor bearing animals, C-309 has emerged as superior to all others. The following %T/C and Log Kill (LK) values were obtained from a single course of IV treatment (Q2d x 5) against early staged SC transplantable tumors of mouse and human origin: Mam 17/Adr [a pgp (+) MDR tumor]: 0%T/C, 3.2 LK; Mam 16/C/Adr [a pgp (-) MDR tumor]: 0%T/C, 3.3 LK; Mam 16/C: 0%T/C, 3.8 LK; Colon 26: 0%T/C, 2.2 LK; Colon 51: 0%T/C, 2.4 LK; Pancreatic Ductal Adenocarcinoma 02 (Panc 02): 0%T/C, 2.4 LK; Human Colon HCT15 [a pgp (+) MDR tumor]: 0%T/C, 3.3 LK; Human Colon HCT116: 0%T/C, 4.1 LK. One additional analog, Cryptophycin-249 (C-249, the glycinate of Cryptophycin-8), also emerged with efficacy rivaling or superior to C-309. However, there was sufficient material for only a single C-249 trial in which a 4.0 LK was obtained against the multidrug resistant breast adenocarcinoma Mam-16/C/Adr. C-309 and C-249 are being considered as second-generation clinical candidates.

The assessment and control of genotoxic impurities (GTI) in pharmaceutical products has received considerable attention in recent years. Molecular functional groups that render starting materials and synthetic intermediates useful as reactive building blocks for small molecules may also be responsible for their genotoxicity. As a potential safety concern, it is important to understand the various issues related to GTIs and how they can be addressed for clinical and commercial phases of development. Justification that these impurities are controlled to safe levels must be obtained during development. This article will briefly discuss the multiple sources of anticipated impurities in a drug substance (also known as active pharmaceutical ingredient or API) synthetic route and how they are identified as GTIs in early chemical process development. A risk-based approach consistent with regulatory expectations is described for establishing control of GTIs. The approach includes process design considerations, impurity rejection information, and appropriate application of specifications. Analytical considerations for determination of GTIs at low levels are also discussed.

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Thioaldehydes containing virtually any -substitutent can be generated by photofragmentation of phenacyl sulfides. Donor-substituted derivatives are reactive toward electron-rich dienes and give 2 + 4 cycloadducts with regiochemistry corresponding to advanced C-C bonding in the transition state. Acceptor-substituted thioaldehydes react in the opposite regiochemical sense with C-S bonding advanced. A number of unusual thioaldehydes have been trapped, including the parent HCH=S, Me3SiCHS, Ph2P(0)CH=S, PhS02CH=S, and CNCH=S, as well as more conventional alkylor acyl-substituted derivatives.

The ICH M7 guidance provides a series of flexible control options for the control of (potentially) mutagenic impurities (PMIs) that fully align with key risk-based principles. This includes option 4, which leverages existing process knowledge and/or data to justify control of PMIs without the need for routine analytical release testing during manufacturing. One such technique highlighted uses systematic, semiquantitative calculations to define the degree of "purge" of PMIs within a synthetic route to an active pharmaceutical ingredient (API) based on physicochemical properties of the impurities in question, and the manufacturing process being undertaken. This paper introduces a consortium-led initiative, Mirabilis, which aims to build on the semiquantitative purge approach, and harmonize industry best practices by enabling the calculations to be conducted in a standardized, consistent, and reproducible manner. The development of an expert-derived knowledge base for the prediction of reactivity by enhancing expert opinion using evidence derived from the published literature and experimental data is also discussed. Furthermore, this paper describes the application of Mirabilis software for the processes involved in the synthesis of verubecestat, naloxegol oxalate, and camicinal.