Simplified analogs

Some of the earliest work in this area was reported by Blechert, who prepared the diastereomeric diols 13.1.1 416) and 13.1.2 417). Both compounds were reported as being able to inhibit the depolymerization of tubulin, but the level of this activity was not reported. An even more simplified set of analogs was prepared by Fuji and Kohno and their collaborators these investigators prepared the analogs 13.1.3-13.1.8, in which the alkyl chain comprised two to seven carbons 418) none of these compounds showed any promising tubulin inhibitory activity. 

The macrolactam 13.1.9 was prepared by Botta and Corelli and their collaborators, based on the observation that an analog lacking the taxol side chain had moderate antiproliferative activity 419). Regrettably 13.1.9, with the taxol side chain in place, did not show any enhanced activity. 

Two analogs which do show interesting activities have been reported recently. The C-aromatic analog 13.1.10 had the same activity as 

The taxol analog 13.1.12 was prepared from deaminoacyltaxine A isolated from Taxus baccata (422). The analog was more cytotoxic than deaminoacyltaxine A, but was significantly less cytotoxic than taxol. 

Several taxol analogs have been prepared in which taxol is linked to another molecule as a dimeric derivative. Thus the dimeric taxanes 13.2.1 and 13.2.2 were prepared by Appendino and Danieli and their colleagues from taxol and 2 -deacetoxyaustrospicatine (423). Although neither compound was cytotoxic, 13.2.2 retained approximately a third of taxol s tubulin-assembly activity. 

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Scheme 46 Diene-ene RCM influence of catalyst activity on the regiochemistry during the synthesis of simplified analogs of sanglifehrin [106b]...

The development of new synthetic methodology has successfully enabled the investigation of structure-activity relationships (SAR) of perylenequinone agents for use in photodynamic therapy. Simplified analogs, such as (M)-96, that have potency equal to the natural product hypocrellin and superior chromophores to improve photoactivation in the therapeutic window were prepared. 

Terry AV Jr, Williamson R, Gattu M, Beach JW, McCurdy CR, Sparks JA, Pauly JR. (1998). Lobeline and structurally simplified analogs exhibit differential agonist activity and sensitivity to antagonist blockade when compared to nicotine. Neuropharmacology. 37(1) 93-102. 

With the exception of compound 75 none of these compounds were active. Since the exocyclic methylene analog 75 had activity we chose to prepare a simplified analog [Fig. (23)]. Thus, the catechol 66 was reacted with 79, K2CO3 and Nal in DMF for 16 h to give the exocyclic methylene compound 80 which lacked the C26 dimethyls. Compound 80 was inactive, which further emphasizes the importance of C26 dimethyls. 

In 2006 the preparation of simplified analogs of natural occurring enediynes, e.g. antitumor antibiotic dynemicin, was reported by Banfi and coworkers. They succeeded in synthesizing two different classes of such compounds where the embedded 10-membered enediyne system is fused either with a (3-lactam ring (lactenediynes) or with an epoxide. Biological tests on these molecules have demonstrated that some representatives are able to cleave the double strand of DNA even at very low concentrations [408]. 

Figure 2.18 The tetradecapeptide somatostatin is a nanomolar-to-subnanomolar ligand of five different somatostatin receptor subtypes. Compounds 62-66 are structurally simplified analogs from four combinatorial libraries, with up to 350 000 members per library. Each compound shows a remarkable selectivity against the different sstl-sst5 receptor subtypes (Table 2.1). The orientation of the compounds follows a projection of their superposition with a Merck cyclopeptide.

The degradation reactions involved in the breakdown of cellulose are clearly highly complex, and thus the use of the concept of property kinetics is a bold simplifying analogy. In property kinetics most of the degradation processes are assumed to be temperature dependent. In addition, most or all of these processes are assumed to affect some useful macroscopic property such as tensile strength so that the individual effects of these processes can be subsumed into one unified effect that obeys the Arrhenius equation. Thus property kinetic studies are necessarily empirical and show a much less obvious or demonstrable mechanistic connection than chemical kinetic studies between the presumed cause and the measured effect. 

Wc note that P E,t) must have the property that i Efi) = 0 and P(Eyt) —> 1 as > oo. H. A. Kramers, Physics 7,284 (1940), has given an approximate solution to this problem based on a simplified analogy to a model for brownian motion in one dimension. 

Baryza JL, Brenner SE, Craske ML, Meyer T, Wender PA. Simplified analogs of bryostatin with anticancer activity display greater potency for translocation of PKCdelta-GFP. Chem. Biol. 2004 11 1261-1267. 

Mass transfer in the film and resin particle are sequential processes and either process may be rate controlling, i.e. the slowest step. By simplified analogy with the previous case for film diffusion, the average flux condition for transfer of ion A in the resin phase may be written ... 

Since 1974, the syntheses of a large number of simplified analogs of strigol have been reported. The vast majority of these analogs retain the structure of the C and D rings of strigol. 

The main representatives of this group are simplified analogs of caliche-amicins/esperamicins aglycons or dynemicin A, respectively characterized... 

Probably more than a thousand of simplified analogs of the alkaloid morphine were investigated. Many of them were just inactive, but it was soon recognized that the phenyl-piperidine unit was crucial for the central analgesic properties (Figure 16.34). In contrast to what was observed for cocaine, no clear discrimination between the analgesic and the narcotic properties could be achieved. 

Before considering the specifics of adsorption design factors, it may be useful to generalize the process with some simplified analogies. 

A computational connection pattern that is formed in (simplified) analogy to biological (cortical) neural networks and used successfully for the classification of unstructured data. Neural networks have a broad range of applications in biology and chemistry (Schneider Wrede, 1998). 

Figure 11-6 represents a simplified analogy mechanism of action for a lovastatin-type drug. 3-Hydroxy-3-methylglutaryl-CoA is reduced to mevalonic acid in two steps, catalyzed by HMG-CoA reductase. It may be suggested that a hypothetical, partially reduced intermediate (in brackets) is reversibly displaced from an assumed enzyme-bound complex by a dihydroxy acid form of lovastatin (derived by hydrolysis of lactone portion of the... 

Santonin (1) has been used as the starting material in the synthesis of simplified analogs of thapsigargin (185) (Figure 5), which is a selective and very potent inhibitor of the microsomal Ca + pumps that can only be isolated in poor yield from Thapsia garganica [36], Studies of structure-activity relationships have revealed that the presence of the 7,11-dihydroxy moiety is important for the Ca2+ pump inhibitory action of 185. 

Based on these observations and in conjunction with reports regarding cycloisodityrosine analogs 196 and 197 showing fairly potent cytotoxicity, the 14-membered cycloisodityrosine moiety is currently considered to be the pharmacophoric unit for this class of natural peptides (160). However, more simplified analogs 198-200 showed no activity, which defined the C-12 amine substituent as also playing an essential role for activity (161). 

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