De novo approaches

In addition to the formation of the pyridine framework by de novo approaches (see section 8.1) or by the cycloaddition/cycloreversion sequence (see section 8.2), one can employ reactions that proceed through a rearrangement pathway. The Boekelheide reaction (see section 8.3.1) involves the rearrangement of an existing pyridine skeleton to a more functionalized scaffold, while the Ciamician-Dennstedt reaction (section 8.3.2) generates the pyridine nucleus by rearrangement of an alternative heterocycle. 

The second extrathermodynamic method that we discuss here differs from Hansch analysis by the fact that it does not involve experimentally derived substitution constants (such as o, log P, MR, etc.). The method was originally developed by Free and Wilson [29] and has been simplified by Fujita and Ban [30]. The subject has been extensively reviewed by Martin [7] and by Kubinyi [8]. The method is also called the de novo approach, as it is derived from first principles rather than from empirical observations. The underlying idea of Free-Wilson analysis is that a particular substituent group at a specific substitution site on the molecule contributes a fixed amount to the biological activity (log 1/C). This can be formulated in the form of the linear relationship ... 

A de novo approach featuring a biocatalytic functionalization step of benzene or bromobenzene (12, x = Br) was reported by Johnson and his group [48]. 

Like classical QSAR, this de novo approach assumes that substituent effects are additive and constant. BA is the biological activity is the jth substituent, which carries a value 1 if present, 0 if absent. The term Uj represents the contribution of the jth substituent to biological activity and p i s the overall average activity. The summation of all activity contributions at each position must equal zero. The series of linear equations that are formulated are solved by linear regression analysis. It is necessary for each substituent to appear more than once at a position in different combinations with substituents at other positions. 

Effenberger and coworkers reported a de novo approach to 5-thio-D-f/zreo-2-pentulofuranose (5-thio-D-xylulose, 20) (Figure 9.7) from 2-mercaptoacetaldehyde, employing rabbit muscle aldolase (RAMA EC 4.1.2.13) and yeast transketolase (EC 2.2.1.1) as the catalysts [32]. 

Scheme 1. De novo approach to galacto-sugar /-lactones from dienoates...

This de novo approach to carbohydrates has also been applied to oligosaccharides (Schemes 9 to 14). Key to the success of this approach is the development of a mild palladium-catalyzed glycosylation (Scheme 6) in combination with the use of the previously developed highly stereoselective enone reduction and dihydroxylation reaction (Scheme 3) as post-glycosylation transformation for the installation of manno stereochemistry 19). 

At the outset we felt that this de novo approach could identify novel agents with improved selectivity toward tumor cells and believed the best way to find these new structures was to initiate structure-activity studies by manipulating functionality at the sugar portion of the molecules. The carbohydrate portion of the... 

Reviewed was the use of our newly developed Pd-catalyzed glycosylation reaction for the incorporation of rare and unnatural sugars on unique biologically relevant structures. This de novo approach for the introduction of carbohydrate structures, under non-Lewis acidic conditions, into preexisting structural motifs is unique. To date, there simply does not exist an equivalent chemical or biochemical method for the stereoselective glycosylation of under-fimctionalized D- and L-sugars, which can be elaborated into a myriad of carbohydrate analogues. Not to mention this method also allows for complete a/(3-stereocontrol. The power and uniqueness of this approach is probably best... 

Set B. The structures and in vitro antibacterial activity of 1,6,7-trisubstituted-l,4-dihydro-4-oxo-l,8-naphthyridine-3-carboxylic acids against S. aureus 209 PJC-l, E. coll NIHJ JC-2, and Ps. aeruginosa Tsuchijima are shown in Table VII.f241 Minimum inhibitory concentrations of B3A - B3C and nalidixic acid (BNA) which are unsubstituted at position 6 are included for comparison. The 18 compoimds represented by BnA, BnB, and BnC where n = 3, 15, 18, and 22 - 24 constitute a set where ethyl is constant at position 1 and the substituent at position 7 is varied consistently (A = pyrrolidinyl, B = piperazinyl, and C - N-methylpiperazinyl) for three different substituents at position 7. This set permits a comparison of both the LFER and de novo approaches. The physicochemical parameters and indicator variables of this set of compounds for the substituents at positions 1, 6 and 7 listed in Tables VIII - X. 

Although de novo approaches would be the best for decoding sequence information from peptide fragmentation spectra, they show sufficient reliability to infer only short sequence tags and thus currently cannot provide a full solution to the identification problem. Nevertheless, they are used in so-called error-tolerant searches that relax the specificity, for instance, by removing molecular mass constraint and thus allowing for matches to DB sequences when there are sequence variations due to mutations or PTMs. 

Figure 18.10 shows the de novo predicted stmcture of a protein. Two cases are involved. Case 1 involves similar stmctures but not similar sequences, and case 2 involves a comparison of the de novo predicted stmcture with its experimentally determined stmcture. Case 1 indicates that the de novo approach provides clues about protein function in the absence of strong sequence homology. Even if we are not entirely sure about the three-dimensional stmcture, the de novo approach allows us to detect the protein function as long as we know the correct sequence. Case 2 aims at determining that the predicted stmcture is identical to the experimental stmcture. 

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