Modern drug discovery often involves screening small molecules for their ability to bind to a preselected protein target. Target-oriented syntheses of these small molecules, individually or as collections (focused libraries), can be planned effectively with retrosynthetic analysis. Drug discovery can also involve screening small molecules for their ability to modulate a biological pathway in cells or organisms, without regard for any particular protein target. This process is likely to benefit in the future from an evolving forward analysis of synthetic pathways, used in diversity-oriented synthesis, that leads to structurally complex and diverse small molecules. One goal of diversity-oriented syntheses is to synthesize efficiently a collection of small molecules capable of perturbing any disease-related biological pathway, leading eventually to the identification of therapeutic protein targets capable of being modulated by small molecules. Several synthetic planning principles for diversity-oriented synthesis and their role in the drug discovery process are presented in this review.

https://science.sciencemag.org/content/sci/287/5460/1964.full.pdf

Target-oriented and diversity-oriented organic synthesis in drug discovery.

Isatins As Privileged Molecules in Design and Synthesis of Spiro-Fused Cyclic Frameworks

Privileged structures have been widely used as an effective template in medicinal chemistry for drug discovery. Chalcone is a common simple scaffold found in many naturally occurring compounds. Many chalcone derivatives have also been prepared due to their convenient synthesis. These natural products and synthetic compounds have shown numerous interesting biological activities with clinical potentials against various diseases. This review aims to highlight the recent evidence of chalcone as a privileged scaffold in medicinal chemistry. Multiple aspects of chalcone will be summarized herein, including the isolation of novel chalcone derivatives, the development of new synthetic methodologies, the evaluation of their biological properties, and the exploration of the mechanisms of action as well as target identification. This review is expected to be a comprehensive, authoritative, and critical review of the chalcone template to the chemistry community.

/pdf/chalcone-a-privileged-structure-in-medicinal-chemistry-2glhtivnj7.pdf

Chalcone: A Privileged Structure in Medicinal Chemistry.

De novo synthesis of substituted pyridines

Synthesis and biological activity of pyrrole, pyrroline and pyrrolidine derivatives with two aryl groups on adjacent positions

Automated parallel synthesis of chalcone-based screening libraries

Solution phase synthesis of a spiro[pyrrolidine-2,3′-oxindole] library via a three component 1,3-dipolar cycloaddition reaction

Aromatic Annulation Strategy for the Synthesis of Angularly-Fused Diterpenoid Quinones. Total Synthesis of (+)-Neocryptotanshinone, (-)-Cryptotanshinone, Tanshinone IIA, and (.+-.)-Royleanone

Total synthesis of dan shen diterpenoid quinones

This paper describes the first total syntheses of the diterpene quinones aegyptinones A and B via an extremely direct route which should easily accommodate the production of gram quantities of each compound. The key step in the synthetic strategy involves the application of a recently developed «second-generation» photochemical aromatic annulation method for the construction of highly substituted aromatic systems. The synthesis of one of the annulation components, the diazo ketone 6, was achieved using a Diels-Alder-based benzannulation strategy employing cyanoallene and the dienamine 13. Cyanoallene proved to be uniquely effective for this cycloaddition, which either failed or proceeded in poor yield using several substituted acetylenes as dienophiles. The pivotal aromatic annulation reaction was accomplished by irradiating a solution of the diazo ketone 5 and the readily available siloxyalkyne 4 in a Pyrex vessel with a 450-W medium-pressure Hanovia lamp at room temperature for 17-20h. The desired tricyclic phenol 3 was produced in 58-70% yield and was then converted to aegyptinone B (2) by treatment with tetra-n-butylammonium fluoride in the presence of oxygen. Finally, cyclization to generate aegyptinone A was accomplished in high yield by brief exposure of 2 to an ethanolic solution of concentrated sulfuric acid at room temperature. Overall, this strategy provides efficient routes (six and seven steps, respectively) to aegyptinones A and B which should facilitate the systematic investigation of the pharmacological activity of these novel diterpenes

David S. Casebier

Papers

Automated parallel synthesis of chalcone-based screening libraries

Solution phase synthesis of a spiro[pyrrolidine-2,3′-oxindole] library via a three component 1,3-dipolar cycloaddition reaction

Aromatic Annulation Strategy for the Synthesis of Angularly-Fused Diterpenoid Quinones. Total Synthesis of (+)-Neocryptotanshinone, (-)-Cryptotanshinone, Tanshinone IIA, and (.+-.)-Royleanone

Total synthesis of dan shen diterpenoid quinones

Total Synthesis of Aegyptinones A and B