Biologically active compounds, nuclei

The benzodiazepine nucleus is extremely important, as it is the base of several drugs and other biologically active compounds with different properties. A facile synthesis of 2-methyl-l,4-benzodiazepin-5-ones has been described by Santagada and co-workers [162]. Isatoic anhydride 254 was reacted with M-substituted allylamines under microwave irradiation to give compound 255... 

How do glucocorticoids and other adrenocorticoids affect the levels of proteins and other biologically important compounds The short answer is that they bind to their receptor in the cytoplasm and that the glucocorticoid-receptor complex travels into the nucleus, where it binds to DMA and affects gene transcription, which increases and, sometimes, decreases the production of important biologically active compounds. The detail of just how the glucocorticoids accomplish this is quite interesting and is depicted in Fig. 44.26. 

It has recently been shown that Vicarious Nucleophilic Substitution (VNS) can be a useful tool for the synthesis of biologically active compounds containing the l,3,4,5-tetrabenz[cd]indole nucleus, such as 6-methoxy-l,3,4,5-tetrahydrobenz [ cd] indole-4-amine [49]. 

Pyrazole nucleus constitutes a number of sub-structures of natural products and biologically active compounds. Several derivatives of these systems find use in medicine described as follows ... 

The indole nucleus is an important scaffold found in many biologically active compounds, and as a result, many methods have been developed for its construction [54], Most of these rely on the assembly of the pyrrole ring on a preformed benzene nucleus. In principle, the indole nucleus could also be assembled by constructing a benzene ring on a preformed pyrrole ring. However, of the methods reported to date, the second method is much rarer. Recently, RCM has been utilized for... 

The indole nucleus (8) is present in a large number of biologically active compounds [25]. 

Indole synthesis is of particular importance, since the indole nucleus is the essential part of many biologically active compounds (alkaloids derived from tryptophane, phalloidin, and so on). Moreover, indole chem-... 

Lactams, and /S-lactams in particular, are interesting owing to their occurrence in biologically active compounds such as antibiotics related to penicillines. Insertion reactions of carbenes offer useful access to poly heterocyclic systems contain a -lactam nucleus, particularly when using rhodium and copper catalysis. Moreover, palladium catalyzed carbonyla-tion of azirines affords )S-lactam derivatives [93] in one step. 

A number of biologically active compounds share basic structural features with 6, and may also function by electron transfer via the iminium moiety. These similarities include the quinoline nucleus conjugated with an unsaturated, often aryl entity, at the 2-position, and a carboxyl group (or derivative) at the 4-position. Cinchophen 7a and derivatives have demonstrated CNS , virucidal, and bactericidal ... 

Cromakalim (137) is a potassium channel activator commonly used as an antihypertensive agent (107). The rationale for the design of cromakalim is based on P-blockers such as propranolol (115) and atenolol (123). Conformational restriction of the propanolamine side chain as observed in the cromakalim chroman nucleus provides compounds with desired antihypertensive activity free of the side effects commonly associated with P-blockers. Enantiomerically pure cromakalim is produced by resolution of the diastereomeric (T)-a-meth5lben2ylcarbamate derivatives. X-ray crystallographic analysis of this diastereomer provides the absolute stereochemistry of cromakalim. Biological activity resides primarily in the (—)-(33, 4R)-enantiomer [94535-50-9] (137) (108). In spontaneously hypertensive rats, the (—)-(33, 4R)-enantiomer, at dosages of 0.3 mg/kg, lowers the systoHc pressure 47%, whereas the (+)-(3R,43)-enantiomer only decreases the systoHc pressure by 14% at a dose of 3.0 mg/kg. 

All of the naturally-occurring monobactams discovered as of this writing have exhibited poor antibacterial activity. However, as in the case of the penicillins and cephalosporins, alteration of the C-3 amide side chain led to many potent new compounds (12). Furthermore, the monobactam nucleus provides a unique opportunity to study the effect of stmctural modifications at the N-1 and C-4 positions of the a2etidinone ring on biological activity. In contrast to the bicycHc P-lactams, these positions on the monocyclic ring system are readily accessible by synthesis. 

The modification and enhancement of biological activity of drugs and hormones by fluorination represent one of the most fruitful recent developments in medicinal chemistry. Its first successes and most interesting subsequent developments were in the steroid field. Almost every new technique of introducing fluorine into organic compounds has been applied in this area and, as a result of both the gross and subtle chemical differences which steroids display at different locations of the nucleus, has produced a wealth of new chemistry. 

It would not be too far fetched to state that life on this planet is totally dependent on two compounds based on the purine nucleus. Two of the bases crucial to the function of DNA and flNA—guanine and adenine—are in fact substituted purines. It is thus paradoxical that the lead for the development of medicinal agents based on this nucleus actually came from observations of the biologic activity of plant alkaloids containing that heterocyclic system, rather than from basic biochemistry. 

Hydrazinopyridazines such as hydralazine have a venerable history as anti hypertensive agents. It is of note that this biological activity is maintained in the face of major modifications in the heterocyclic nucleus. The key intermediate keto ester in principle can be obtained by alkylation of the anion of pi peri done 44 with ethyl bromo-acetate. The cyclic acylhydrazone formed on reaction with hydrazine (46) is then oxidized to give the aromatized compound 47. The hydroxyl group is then transformed to chloro by treatment with phosphorus oxychloride (48). Displacement of halogen with hydrazine leads to the formation of endralazine (49). ... 

Dodds, E.C. and Lawson, W. (1938). Molecular structure in relation to oestrogenic activity. Compounds without a phenanthrene nucleus. Proceedings of the Royal Society of London, Series B Biological Sciences 125, 222-232. 

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