The synthesis of the core unit of cycloaraneosene and ophiobolin M has been investigated, following a general strategy applicable to both 5−8 bicyclic systems. The synthetic strategy includes a ring-closing metathesis reaction to generate the central eight-membered ring as well as a palladium-mediated coupling of a Grignard reagent to introduce [a]

This work describes the preparation of approximately 13,000 compounds for rapid identification of hits in high-throughput screening (HTS). These compounds were designed as potential serine/threonine or tyrosine kinase inhibitors. The library consists of various scaffolds, e.g., purines, oxindoles, and imidazoles, whereby each core scaffold generally includes the hydrogen bond acceptor/donor properties known to be important for kinase binding. Several of these are based upon literature kinase templates, or adaptations of them to provide novelty. The routes to their preparation are outlined. A variety of automation techniques were used to prepare >500 compounds per scaffold. Where applicable, scavenger resins were employed to remove excess reagents and when necessary, preparative high performance liquid chromatography (HPLC) was used for purification. These compounds were screened against an 'in-house' kinase panel. The success rate in HTS was significantly higher than the corporate compound collection.

We present a novel combination of generative and predictive machine learning models for discovering unique protein inhibitors. The new method is assessed on its ability to generate unique inhibitors for the cancer associated protein kinase, CDK9. We validate our method by performing biochemical assays, attaining a hit rate of more than 10%, demonstrating the method to be a notable improvement upon a more standard, and somewhat naive approach. Moreover, we imposed the additional challenge of finding inhibitors that are readily synthesized. Importantly, two new inhibitors are found, with one being distinct from reported CDK9 inhibitors. We discuss the results in the context of modern machine learning principles and the desire expressed by the rational drug design community to secure molecules that are structurally different, yet with high binding affinities, to structurally determined protein targets.

Terpenes Terpenes U 0200Studies Towards the Total Synthesis of Cycloaraneosene and Ophiobolin M: A General Strategy for the Construction of the 5-8 Bicyclic Ring System. -A general and effective method to prepare the 5-8 bicyclic ring system present in many natural products is developed. The key steps are ring-closing metathesis, introduction of a methyl group at the ring junction, and alkylation of the triflate (VII). -(RUPRAH, P. K.; CROS, J.-P.; PEASE, J. E.; WHITTINGHAM, W. G.; WILLIAMS*, J. M. J.; Eur.

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