DIVERSOMER^TM technology: Solid phase synthesis, automation, and integration for the generation of chemical diversity

Abstract

The drug discovery process depends upon the synthesis and testing of thousands of compounds to bring a new drug through discovery, clinical testing, development, and FDA approval. Recent advances in high throughput screening have created the need for the accelerated synthesis of small organic molecules. By combining solid phase chemistry, organic synthesis, and automation with a unique apparatus capable of'performing techniques common to organic synthesis, "libraries" of organic compounds ( D I V E R S O M E R S~~) are efficiently generated. This was demonstrated by the multiple simultaneous synthesis of 40 hydantoins and 40 benrodiazepines, related to Dilantina and ValiurnB, respectively.

Development of Weiner et al. Force Field Parameters Suitable for Conformational Studies of [1,4]-Benzodiazepines and Related Compounds

“…10 In this manner, bond parameters consistent with the existing Weiner et al parameters were obtained for all relevant bonds in [1,4]benzodiazepines. We also estimated bond constants for substituents on aromatic rings.…”

“…As a reference, the same calculations were performed with Tripos 6.0 general use force field, 33 obtaining an RMSD av of 0.140 Å. It is evident that any of the three parameter sets reported here predicts the experimental structures of [1,4]-bezodiazepines more precisely than a more general force field. Among the three new sets, structures minimized with parameters developed using the AM1 semiempirical had, on average, the smallest deviation from experimental structures, and these parameters were therefore chosen to complement the existing parameter set for modeling [1,4]-bezodiazepines with the Weiner et al force field.…”

“…Smaller values of RMSD av indicate a better agreement between experimental and calculated structures. The values obtained for a set of 30 [1,4]-benzodiazepines were 0.091, 0.095, and 0.096 Å for parameters derived using AM1, PM3, and linear interpolation, respectively. As a reference, the same calculations were performed with Tripos 6.0 general use force field, 33 obtaining an RMSD av of 0.140 Å.…”

“…R ij is the interatomic distance between atoms i and j, and q i , q j , and are the electrostatic charges of atom i, atom j, and the dielectric constant, respectively. To extend the force field to [1,4]-benzodiazepines, nonbonded parameters were assigned for several new atom types not implemented in the Weiner et al model. Bonded parameters K bs , l o , V, F, and n were calculated for all bonds containing new atoms and for bonding topologies between existing atoms not originally described in the force field.…”

Solid-Phase Synthesis of Seven-Membered Heterocycles with Two Nitrogen Atoms

“…Later, silicon was replaced with germanium, resulting in an easy electrophilic demetalation, which significantly increased the tolerance level of the sequence toward diverse functional groups [24]. In 1993, DeWitt reported a three-step traceless synthesis of 1,4-benzodiazepines from polymer-supported amino acids 47 and 2-amino benzophenone imines 48 [25,26]. To obtain the final compounds, resin 49 was treated with neat TFA at an elevated temperature, which caused the consecutive cleavage and cyclization to 50 (Scheme 8).…”