Enhancements of screening collections to address areas of unmet medical need: an industry perspective

Diastereoselective synthesis of novel heterocyclic scaffolds through tandem Petasis 3-component/intramolecular Diels–Alder and ROM–RCM reactions

“…In recent years, it has become apparent that traditional screening collections, which are largely dominated by 'flat' (sp 2 -rich), small molecules lack the structural complexity and diversity required to target more challenging biological targets such as protein-protein interactions, transcription factors and nucleic acid macromolecules. 2 Aiming for a better coverage of biologically relevant chemical space, 3 strategies relying on concise and efficient synthetic pathways for the generation of structurally diverse molecular libraries, featuring a higher content of sp 3 -hybridization, scaffold complexity and functional group diversity have been developed. 4 Importantly, while providing access to molecular frameworks that mimic the structural complexity of natural products, these strategies focus on enabling the synthesis of structural analogs to allow for a smoother downstream optimization and advancement of screening hits.…”

“…However, the use of methyl Meldrum's acid (isopropylidene 2-methylmalonate) 7 effectively solved this triethylamine proved impossible to remove. Reductive amination of the secondary amine with NaBH(OAc) 3 proceeded smoothly with both aromatic and aliphatic aldehydes to give 10 in good yields ( Table 2). The primary hydroxyl group was then arylated with a set of phenols using the Mitsunobu reaction.…”

“…Satisfyingly, also the benzyl-and methylsubstituted amines (8e and 8g, respectively) readily underwent ROM-RCM to give the corresponding products 13b and 13d in 72% and 65% yield (entries 3 and 5), respectively. Interestingly, the ROM-RCM reaction of benzyl-, 2,4-dimethoxybenzyl (DMB)-and methyl-substituted amines took place in the absence of hydrochloric acid when the reaction was conducted in refluxing toluene (entries [3][4][5]. Under these conditions the yield of 13b was improved to 80%, 13c was isolated in 76% yield (entries 4 and 5, respectively), while 13d was isolated in slightly lower yield (56%) (entry 5).…”

Phytocosmetics – where nature meets well-being

“…In a simple analysis, a high degree of activity and bioavailability are expected from these properties, and, therefore, their possibility of interaction with receptor sites and transporter systems are potentially higher than synthetic options, at least those not related to natural structures, as some studies have indicated. [4][5][6] Although the focus of the pharmaceutical industry for botanicals and other natural products has been reduced in the last years, 3,4,7 natural molecules still are the main source of potential drugs and many natural products still figure in clinical trials or at least inspire new drug candidates, especially for anticancer and antimicrobial research. 3,4 It may be expected that some important new approaches and technological improvements, like recent advances in NMR and mass spectrometry, "omics" and high-throughput screening (HTS), will bring new stimulus in this field.…”

Nature’s bounty of natural products brings bewildering outcomes

“…Natural product libraries show a wide assortment of pharmacophores and are rich in stereochemistry. Such advantages lead to hits, even against the more difficult screening targets, such as protein-protein interactions (Drewry and Macarron, 2010). Importantly, natural products are -natural metabolites‖, and by definition must possess metabolite-likeness.…”