Combinatorial synthesis and screening of heterocyclic druglike scaffold libraries

Most drug molecules clearly fall in the category of non-oligomeric, small-sized, hetero-cyclic molecules. Thus, exploitation of combinatorial technology for drug discovery can be expected to rely heavily on the ability to generate chemical libraries of such molecular entities. Solid-phase synthesis (SPS) makes a scaffold amenable to split-pool protocols, and also offers general advantages such as driving difficult reactions to completion through the employment of excess reagents, and easy purification of desired immobilized products from unwanted reagents and side-products in solution. A consequence of this has been a frenzy of activity from various laboratories aimed at translating all important solution-phase chemistries of historical drug-like molecules into corresponding solid-phase and combinatorial formats. Unlike the synthesis of linear, oligomeric peptidic and non-peptidic libraries described so far, heterocycles are non-polymeric scaffolds and are usually constructed from diverse building blocks employing nonrepetitive chemistry.

One of the first examples in this category was reported by Ellman and co-workers [23] through the preparation of libraries of benzodiazepines, an important heterocyclic class of pharmaceutical agents (Fig. 4). The synthesis proceeds through the intermediacy of 2-aminobenzophenone BBs 14 attached on an acid cleavable linker bearing solid support through a hydroxyl or carboxyl group of the aryl moiety. The parallel synthesis of a 192-member 1,4-benzodiazepine library 15 comprising analogs with diverse chemical functionalities such as amides, amines, phenols, carboxylic acids and indoles was performed [24].

Screening Synthesis
Fig. 4. Bioactive molecules from the synthesis and screening of drug-like scaffold, small-molecule libraries.

Upon screening for binding to the cholecystokinin A receptor using a competitive radio-ligand binding assay, detailed structure-activity relationship (SAR) data were acquired, from which the indole analog 16 was identified as a potent CCK ligand library member. The limitation of the scarce availability of 2-aminobenzophenone BBs has been recently overcome by developing a more facile method for constructing 2-aminoaryl ketone deriva tives on solid support using palladium-mediated Stille coupling between 2-aminoaryl stannane on solid support and an acid chloride as the solution coupling partner [25]. Thus, the need for aminobenzophenone BBs in the overall synthesis is replaced by the readily available acid chlorides. More recently, the modified synthetic protocol has been utilized for preparing an 11 200-analog library from 20 acid chlorides, 35 AAs, and 16 alkylating agents [26].

An alternate synthetic strategy for benzodiazepines involves the condensation of resin-bound a-amino esters 17 with 2-aminobenzophenone imines followed by TFA treatment of the intermediate to effect cleavage and cyclization [27]. The parallel synthesis of 40 discrete benzodiazepine analogs 18 was performed, and expected SAR data were generated in a bioassay based on the inhibition of fluoronitrazepam (Fig. 4).

Resin-bound a-amino esters 17 react cleanly with aromatic and heteroaromatic aldehydes at room temperature in neat trimethyl orthoformate to afford the corresponding imines 20. Lewis acid mediated ionization of these immobilized imines leads to a-amino aldimines which undergo chelation-controlled regio- and stereoselective [3 + 2] cycloaddition with a wide variety of electron-deficient olefin dipolarophiles to yield the five-membered pyrrolidines. A pool of pyrrolidines prepared combinatorially from four AAs, five aromatic aldehydes, and four olefins was acylated with three different mercaptoacyl chlorides to provide, after appropriate deprotections and final TFA cleavage from resin, a library of >480 mercaptoacyl proline analogs 21. Such molecules have found well-pre-cedented use as inhibitors of ACE, as exemplified by the antihypertensive drug Captopril. Serial deconvolutive screening of this library for activity against ACE led to the identification of 22 (Ki= 160 pM) as an analog 3 times more potent than Captopril [28].

Diketopiperazines (DKPs) are a well-studied class of dipeptide mimetics that have shared a great deal of history and success in the pharmaceutical industry. Recently, a three-step SPS of a 1000-member (103) DKP library 24 employing two different sets of 10 AAs and one set of 10 aldehyde BBs has been reported (Fig. 4) [29]. Starting from resin-bound secondary amines 23 derived from sodium triacetoxyborohydride-mediated reductive alkylation of the amino group of immobilized a-amino esters 17 with aldehydes, PyBrop-mediated double coupling with the next set of Boc-protected AAs provides the penultimate dipeptide precursors. Boc removal with TFA followed by a short reflux in toluene to induce ring cyclization and simultaneous cleavage from the solid support afforded the desired DKPs 24 in solution as 10 pools with 100 members in each pool. Iterative screening and resynthesis of this library has led to several bioactive molecules, as exemplified by the identification of a neurokinin-2-receptor ligand 25 (IC50= 313 nM) [3].

The dihydropyridine (DHP) scaffold has surfaced in numerous diverse bioactive molecules, the most successful examples being calcium channel blocker antihypertensive drugs such as Nifedipine and Nimodipine. A facile synthetic route for the SPS of DHPs proceeding through the intermediacy of immobilized P-keto esters and P-enamino esters 26 has recently been described by Gordeev and co-workers [30]. This methodology was extended toward the preparation of a 100-member DHP library 27 comprising 10 pools, with each pool bearing a distinct aryl group and 10 different R1/R2 substituents derived from the 10 P-keto esters employed for forming enamino esters. Serial deconvolutive screening for calcium channel blockade activity using a cortex membrane binding assay identified several active compounds including the commercial drug Nifedipine 28 (IC5o = 18 nM). This example represents a significant departure from conventional solid-phase and combinatorial chemistry in the sense that it does not utilize any AA building blocks in the construction of the core scaffold.

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  • Faruz
    Why scaffold important in combinatorial chemistry?
    2 years ago

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