Side Chain-Modified Analogs

A variety of side-chain modified analogs of MDMA and MBDB have begun to be examined. Very early studies were of the a,a-dimethyl analog, 3,4-methylenedioxyphentermine (figure 8a) and its N-methyl derivative (figure 10). This latter compound proved to lack MDMA-like activity (Shulgin, unpublished). Interestingly, this compound also lacked the ability to stimulate the release of [ H] serotonin from prelabeled rat brain synaptosomes (Nichols et al. 1982). 

Out of 350 epothilone analogs produced at Schering AG (now Bayer) by total synthesis up to 2006, the side chain-modified analog sagopilone (also known as ZK-EPO, 3 Figure 3.2) was chosen as a clinical candidate, since it combined high activity and efficacy with fast and efficient cellular uptake and... 

Other Potent Side Chain-Modified Analogs... 

In addition to analogs incorporating an olefinic double bond as a linker between the macrolactone ring and different types of heterocycles, we have also studied a new family of side-chain modified structures, which are characterized by rigidifica-tion of the entire side-chain manifold (exemplified for quinoline-based analogs 30 and 31). ... 

Functional group transformations of the /3-lactam form of the taxol side chain precursor have also been investigated. For example, both the Ojima and the Georg groups showed that N-(r-Boc) -lactams can be converted to other N-acyl /3-lactams in very good yield without losing optical purity. These transformations allowed preparation of various side chain modified taxol or docetaxel analogs (246, 247, 248). 

In addition to the examples discussed above, many other potent side chain-modified epothilone analogs have been reported in the literature. Major advances in this area have resulted from the collaborative work between the Nicolaou group at the TSRI and the group at Novartis. For example, these groups discovered that pyridine-based analog 22 (Figure 3.5) is equipotent... 

An early application of the anionic oxy-Cope rearrangement in steroid synthesis was documented by Koreeda (Equation 15) [89], (20R)-Desmosterol (129) was efficiently accessed in 94% yield as a single isomer after [3,31-rearrangement of the potassium alkoxide of 128. The product provided a versatile intermediate for the synthesis of vitamin D metabolites and steroids incorporating modified side chains. In analogy with the case of the pronounced rate differences seen for the diastereomeric pair 125 and 127, the corresponding C,6-epimeric alkoxide failed to participate in an equivalent [3,3]-rearrangement. 

Scheme 81 ROCM performed on epoC (237c), an unstrained natural macrocycle synthesis of epoC analogs with modified side chain [171]...

Most relevant for the affinity for A9-THC and analogs to CB-receptors are the phenolic hydroxyl group at C-1, the kind of substitution at C-9, and the properties of the side chain at C-3. Relating to the structure-activity relationships (SAR) between cannabinoids and the CB-receptors, many different modified strucfures of fhis subsfance group were developed and fesfed. The most important variations include variations of the side chain at the olivetolic moiety of the molecules and different substitutions at positions C-11 and C-9. One of the most popular analogous compounds of A9-THC is HU-210 or (-)-trans-ll-OH-A8-THC-DMH, a cannabinoid with a F,l-dimethylheptyl side... 

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