Mini Reviews in Medicinal Chemistry - Volume 6, Issue 1, 2006

Solid-phase chemistry has been used for the synthesis of organic molecules for more than 30 years. However, this powerful approach remained unappreciated until the work by Bunin and Ellman in 1992 on solid-phase synthesis of arrays of 1,4-benzodiazepine-2-ones. Similar work on other drug-like molecules followed and a major revival in the study of solid-phase organic synthesis (SPOS) began. For developing high throughput synthesis, chemistry on a solid support is attractive from different perspectives: (i) filtration can be used for rapid purification; (ii) excess reagents can be used so the reactions can be driven to completion; (iii) automation is easily accomplished; and (iv) relative site isolation is achieved getting the "pseudo-dilution effect" which makes intramolecular macrocyclization a suitable reaction that could be carried out efficiently on solid-phase rather than in solution. Nowadays, combinatorial synthesis of small organic molecules using solid-phase approaches is recognized as a powerful tool for the rapid development of novel lead compounds and for the optimization of therapeutic efficacy. The present issue of Mini-Reviews in Medicinal Chemistry consists of eight invited review articles that cover different areas of research dealing with the application of SPOS to the preparation of biologically interesting compounds. The first article of this issue by A. Ganesan describes recent achievement of his group in different aspects of solid-phase synthesis including synthesis of unsymmetrical guanidines, tetrahydro-β-carbolines and kahalalide A. In the next article, Cironi, Alvarez and Albericio present an overview of recent examples of the use of chemistry on solid support in the preparation of non-peptidic natural products and related compounds. In the third article, gives an update on the application of solid-phase methodologies for the preparation of biologically interesting compounds containing hydroxamic acid moiety. The fourth article by Poirier and Maltais provides a comprehensive review on the solid-phase synthesis of steroidogenic enzyme inhibitors and steroid receptor modulators. Next, Kamal and colleagues contribute with two reviews dealing with the recent advances in the solid-phase synthesis of benzodiazepines in their first article, and quinoxaline, quinazoline and benzimidazole in their second article. In the seventh article, Pettersson, Clotet-Codina, Este, Borrell and Teixido give a compilation of the combinatorial methodologies applied to the development of anti-HIV drug. In the final article, we provide an update on the application of solid-phase and combinatorial synthesis to the preparation of β-lactam compounds. Finally, I would like to express my sincere thanks to the authors, all experts in their fields, for setting aside time to write these excellent reviews that give prestige to this issue. It has been an honor for me to work with such outstanding scientists. I fully anticipate that their effort will be appreciated by the scientific community interested in this important area of research.

Solid-phase synthesis is a powerful tool for achieving high-throughput chemistry. This review discusses recent diverse examples from my group: the solid-phase synthesis of unsymmetrical guanidines, polymer-supported versions of cyclooctadiene and 9-BBN, a triflate-like linker, the synthesis of tetrahydro-β-carbolines by the acyliminium Pictet-Spengler reaction, and a total synthesis of the antimycobacterial cyclic depsipeptide natural product kahalalide A.

Solid-phase chemistry, first introduced for peptide synthesis in the 1960's, has become an integral part of organic synthetic methodology. Presented herein is an overview of recent examples of the use of solid-phase in the preparation of non-peptidic natural products and related compounds, encompassing on-resin total syntheses as well as the use of polymer-supported reagents in solution.

Chemical strategies developed for the solid-phase synthesis of hydroxamates are divided into four groups: (i) the traditional synthesis of hydroxamates via cleavage of resin-bound esters by hydroxylamine and its derivatives, (ii) introduction of hydroxamic acid moiety on the resin-bound precursor, (iii) transformation of polymer-supported hydroxylamine, attached to a solid supported linker either by oxygen (O-linking strategy) or by nitrogen (N-linking strategy), and (iv) synthesis of N-alkyl hydroxamates. The scope and limitation of individual approaches are discussed.

Estrogens and androgens are key growing factors involved in a large series of disorders. Two main strategies are possible for controlling their undesirable agonist effects: (1) blocking their biosynthesis by using selective enzyme inhibitors, and (2) antagonizing their hormonal action on a receptor with an antiestrogen or an antiandrogen. In this review, we will briefly discuss the identification of a series of important therapeutic targets, through the study of steroidogenesis of potent estrogens, estrone and estradiol, and potent androgens, testosterone and dihydrotestosterone, as well as of their nuclear receptors. We will next review the solid-phase synthesis of steroidogenic enzyme (steroid sulfatase and 17β-hydroxysteroid dehydrogenases) inhibitors and steroid (estrogen and androgen) receptor modulators, all being potential therapeutic agents for the treatment of hormone-sensitive diseases.

Benzodiazepine based heterocycles can be prepared efficiently on solid-support by employing different approaches. In this review, an effort has been made to highlight academic and industrial examples of combinatorial synthesis for this type of heterocycles published in the last decade. Therefore, it describes synthetic strategies for the generation of benzodiazepine privileged structures employing the corresponding resin-bound substrates. Further, the most relevant biological properties of these heterocycles have also been incorporated.

Quinoxaline, quinazoline and benzimidazole based templates have been synthesized on solid-support employing different methodologies. This review enlightens academic and industrial examples of combinatorial synthesis for this type of heterocycles that appeared in the literature in the last decade. Hence, some of the important synthetic strategies for the generation of quinoxaline, quinazoline and benzimidazole based privileged structures, and the important biological activities for these heterocycles have been highlighted. Further, benzothiadiazinone, thioxoquinazolinone, cinnoline and indazole are also examined in this review.

A compilation of combinatorial chemistry techniques applied to anti-HIV drug development is presented in this review. This synthetic strategy together with high throughput screening assays has allowed the discovery and optimization of novel lead anti-HIV compounds.

Solid-phase organic synthesis (SPOS) has become an effective synthetic tool for the preparation of combinatorial libraries of non-oligomeric small molecules. Owing to their high efficacy and extremely safe toxicological profile, β-lactam antibiotics are the first choice for bacterial infectious diseases. Moreover, β-lactam compounds have also showed other biological activities that include inhibition of prostate specific antigen, thrombin, human cytomegalovirus protein, human leukocyte elastase and cholesterol absorption. Thus, the application of combinatorial and related methodologies to the chemistry of the β-lactam ring has been recognized as a very attractive challenge by different research groups around the world. This review covers the solid-phase and combinatorial chemistry related to mono-and multicyclic β-lactam compounds that has been reported in the literature from 1999 to 2004.