Diversity Oriented Organic Synthesis of Biologically Important Molecules

Abstract

One of the major goals in drug discovery research is to identify high affinity and specific ligands for receptors and enzymes. The identification of such ligands is an important step in the development of molecular probes for the study of receptor and enzyme function and finally eventual development of therapeutic agents. Mechanism based approaches to the discovery of novel, selective, small molecules that disrupt specific cellular mechanisms have dominated pharmaceutical research for decades. Several groups in the world have started their launch in synthesizing small molecule libraries. Among them, Schreiber, Nicolaou, Schultz, Shaw, Spring and Arya’s groups are actively involved in this emerging field. There are a number of potential sources of small molecule collections. Nature has traditionally been a rich source of small molecules that effect biological systems, many of which act on specific protein targets. Combinatorial libraries are alternative sources of small molecules. Combinatorial chemistry is one of the important new methodologies developed by organic and medicinal chemists to reduce the time and costs associated with producing effective and competitive new drugs. By accelerating the process of organic synthesis of small molecules this method is having a profound effect on drug discovery. The basic principle of combinatorial chemistry is that a large range of analogues on a given pharmacophore is synthesized using the same reaction conditions. In this way, the chemists can synthesize many hundreds or thousands of compounds in one time instead of preparing only a few by simple synthetic methodology. Although using combinatorial chemistry vast numbers of compounds can be synthesized, presently this methodology is not as successful as initially expected in drug discovery research. The failure of this approach to discover a broad range of activities may be due to the lack of structural diversity of the products obtained by the approach. In combinatorial chemistry, any structural diversity of the products is only supplied by the building blocks and starting scaffolds, while the resulting molecular framework are the same in every case. Thus, although combinatorial chemistry will undoubtedly continue to lead to identification of additional biological agents, the level of structural diversity that is achieved using this technique is not sufficient to complement the wide variety of modern biomedical targets. The appendage diversity that is achieved by varying substituents around a common core is thought to limit the compounds to a narrow “chemical space”. Very often, and particularly in the pharmaceutical company setting, the molecules accessed in this manner are designed to fall within defined physico-chemical parameters that increase their chances of becoming drug candidates. For example, the well known Lipinski rules for drug-like molecules consider properties aimed at increasing bio-availability (molecular weight, solubility, number of hydrogen-bond donors and acceptors, etc). Natural products and combinatorial libraries provide only a small proportion of bioactive chemical space. So in order to exploit compounds from the unexplored areas of chemical space, synthesis of an array of small molecules with high level of structural diversity to interrogate wide areas of chemical space simultaneously is required. In order to achieve the highest levels of structural diversity: (i) the building blocks, (ii) the stereochemistry, (iii) the functional groups and, most importantly, (iv) the molecular framework must be varied. The question of synthesizing structurallydiverse collections of small molecules arises due to the fact that compounds that have the same structural diversity often have a similar biological profile within a few orders of magnitude, although there are exceptions. The need for novel, chemically diverse small molecules that are capable of selectively modifying the function of the majority of biological targets in the human cell is rapidly growing in the modern biomedical research. Since the number of relevant biological targets continues to grow as a result of intense research, this important goal can only be achieved by effectively integrating the development of new synthetic technologies to generate novel chemically diverse entities, with assays against a broad range of biological targets. New synthetic technologies encompass methods for more efficient synthesis of small molecules, their purification, isolation and characterization. The efficient synthesis of structurally diverse small molecules has been distinguished from targetoriented synthesis (e.g. natural product synthesis and focused ‘library’ synthesis) and it is termed diversity oriented synthesis (DOS). As the phrase itself describes, this is a concept to synthesize a diverse range of small molecules using the synthetic tools. The idea was conceived by Stuart L. Schreiber. Through diversity-oriented synthesis, one can achieve more structural complexity than in the early days of combinatorial chemistry. Preparation of structurally complex and diverse molecules results in a broader population of chemical space and facilitates effective probing of biological space. While target oriented syntheses are used in drug discovery efforts involving preselected protein targets, diversity oriented syntheses are used in efforts to identify simultaneously therapeutic protein targets and their small molecule regulators. Target oriented synthesis has benefited from a powerful planning algorithm named retrosynthetic analysis; a comparable algorithm for diversity oriented synthesis is only now beginning to be developed. Planning diversity oriented syntheses will become increasingly important for organic chemists as methods to screen large collections of small molecules become more effective and routine. The thesis entitled “Diversity Oriented Organic Synthesis of Biologically Important Molecules” is organized under six main chapters: Chapter 1: Role of Diversity Oriented Organic Synthesis of Small Molecules in Drug Discovery Research In the Chapter 1, an overview of diversity oriented synthesis (DOS) is given. The Chapter describes modern drug discovery process along with the all tools to explore it. An adequate discussion about the of role of small molecules derived from natural products, combinatorial chemistry and diversity oriented synthesis (DOS) along with the recent examples of DOS is also given. Chaper 2: Synthesis of Unsymmetrical Triarylmethanes and 9-Arylxanthenes by Friedel-Crafts Diarylmethylation of Electron-Rich Arenes This chapter is divided into two sections: Sections 2A and 2B. In the Section 2A, a short and easy synthetic route for the preparation of unsymmetrical TRAMs containing pyridine, thiophene and furan rings is described. The synthesis of a new series of trisubstituted methanes (TRSMs) containing a thioether group is also described. We believe that this research work regarding the synthesis of TRAMs containing these heterocycles would further expand applications of TRAMs. Section 2B describes our effort to develop a new synthetic route for the preparation of unsymmetrical 9-arylxanthenes. In this research work we have demonstrated a new synthetic route of 9-arylxanthenes by FeCl3 catalyzed diarylmethylation of electron rich arenes. The reaction was driven by cationic activation of diaryl carbinols containing tethered arenoxy groups by 10 mol % FeCl3. It is important to mention that our synthetic strategy could allow significant variation of all the aryl rings of 9-arylxanthenes and thereby producing symmetrical as well as unsymmetrical 9-arylxanthenes which are not easily available using the previously published methods. Chapter 3: Synthesis of [(Aryl)arylsulfanylmethyl]pyridines (AASMPs) as a New Class of Antimalarial Agents Chapter 3 deals with our study which has identified AASMPs as a new class of TRSMs with antiplasmodial activity both in vitro and in vivo. Our work also indicates that among all [(aryl)arylsulfanylmethyl]heteroarenes (AASMHs) only those with a pyridine ring i.e. AASMPs show antimalarial activity. AASMHs containing furan or thiophene rings are inactive. Interestingly, AASMPs exhibit acceptable selectivity against the malaria parasite and show antimalaria activity in vivo against the MDR rodent malaria parasite P. yoelii. Chapter 4: Design, Synthesis and Antitubercular Activity of Diarylmethylnaphthol Derivatives Chapter 4 describes our design, synthesis and antitubercular activity of a series of diarylmethylnapthyloxy ethylamines. ortho-Substituted diarylmethylnapthyloxy ethylamines were found to be more active than their para- substituted counterparts. Five of the ortho- substituted diarylmethylnapthyloxy ethylamines showed promising activity in vitro. It is conceivable that these triarylmethane derivatives containing naphthalene ring might act as a lead for optimizing antitubercular activity. Chapter 5: Enantioselective Synthesis of Natural Product-Like Benzo-Annulated Oxa-Heterocycles This chapter is divided into two sections: Sections 5A and 5B. Section 5A deals with our efficient diversity oriented enantioselective synthesis of “natural product like” benzo-annulated oxa-heterocycles 2,3-dihydrobenzofuran and 1-benzopyran using β-hydroxy-α-tosyloxy esters as chiral building blocks which are easily accessible through regioselective α-tosylation of Sharpless asymmetric dihydroxylation-derived syn-2,3-dihydroxy esters. The ease of the reaction sequence, as well as the commercial availability of large array of starting 2-hydroxyaromatic aldehydes, makes this process a practical method for the preparation of “natural product like” 2,3-dihydrobenzofuran and 1-benzopyran derivatives. In addition, the scope the reaction sequence is much broader, and the synthesis of various substituted aromatic and heteroaromatic nuclei can be envisioned from the starting 2-hydroxy aldehydes. Section 5B describes an asymmetric synthesis of a natural product-like 2- substituted 1-benzoxepine derivative. Key steps include Sharpless asymmetric dihydroxylation reaction on suitable α,β-unsaturated ester and construction of the 1- benzoxepine nucleus by phenoxide ion-mediated intramolecular ring opening of 7- endo-tet α,β-dihydroxy ester cyclic sulfate. To the best of our knowledge this is the first use of α,β-dihydroxy ester cyclic sulfate in benzo-annulated heterocycle synthesis. Chapter 6: Total Synthesis of Spisulosine: A Potent Anticancer Agent from Marine Calm Spisula Polynima Chapter 6 describes a new asymmetric total synthesis of anticancer natural product spisulosine starting from commercially available palmityl alcohol. Notable feature of this approach includes the use of Sharpless asymmetric dihydroxylation of an allylic chloride derivative to synthesize an enantiomerically pure epoxy alcohol and regioselective epoxide ring opening of the protected epoxy alcohol. The synthetic strategy described in this chapter for spisulosine might be easily amenable for the preparation of either enantiomer depending on the use of AD mix β or α and also its other diastereoisomer. The other merits of this synthesis are high-yielding reaction steps, high enantioselectivity and various possibilities available for structural modification and thus it might be considered as a general synthetic strategy to enantiomerically pure 2-amino-3-alkanols.