Sarcodictyin

Some research groups have derivatized biological active and very important natural products (Scheme 3.30) like Indolactam V (207) [297], Sarcodictyin (208) [298] Taxol (209) [299] and Vancomycin (210) [123]. For example, the soHd-phase synthesis of Indolactam derivatives (213) with three points of diversity has been reported by Waldmann et al. in 1999 (Scheme 3.31) [297]. 

Anticancer sarcodictyin A/diterp. semisynthesis from sarcodictyin A, from waiting for development ... 

O It, P. t NMe J fol te CH(OMe)j sarcodictyin A analogue marine Sarcodictyon roseam (Philippi, 1842) [= Rolandia rosea (Philippi)], Stolonifera, as well as certain Pennatulacea and Alcyonacea, Cnid. Nicolaou 1998... 

The addition of LiCl and Cul, and triphenylarsine as ligand are required to suppress side-reactions in the carbonylative cross-coupling of geminally substituted alkenyl triflate in the synthesis of sarcodictyin. Stereochemical configuration of the double bond of organotin compound was completely lost in this reaction (Equation (5)). " ... 

The Kharasch reaction has also been employed by Gennari and coworkers to synthesize, from (i)-carvone, a potential functionalized precursor of sarcodictyins and eleuther-obin (Scheme 62). 

Hamel, E., Sackett, D. L., Vourloumis, D., and Nicolaou, K. C. (1999). The coral-derived natural products eleutherobin and sarcodictyins A and B Effects on the assembly of purified tubulin with and without microtubule-associated proteins and binding at the polymer taxoid site. Biochemistry 38, 3490-3498. 

The 4,7-oxaeunicellane skeleton of the eleutherobins is also found in the eleuthosides (2, 3), the sarcodictyins (4), and the valdivones (5) (Figure 1) [4-6]. While the arabinosyl residue is not required for an antitumor effect, the methylurocanic acid ester side chain bound to C8 is part of the pharmacophore. Recent progress in the total synthesis of eleutherobin is discussed together with the identification of a common pharmacophore for tubulin-binding natural products, and a combinatorial way to determine the structure/activity relationship and drug optimization. 

Fig. 1. Molecular structures of eleutherobin, eleuthosides, sarcodictyins, and valdivone.

Structure/activity relationship studies on the sarcodictyin library are performed by induction of tubulin polymerization and by cytotoxicity studies with three cancer cell lines, including Taxol-resistant lines. Derivatives that induce tubulin polymerization more strongly than the natural product sarcodictyin have been determined, and can show higher cytotoxicity even as far as Taxol-resistant tumor cells are concerned. The results of the structure/... 

Fig. 4. Attachment of the pharmacophoric side chains to the sarcodictyin core structure by combinatorial synthesis.

For building up a library around a given core structure many examples have been given, e.g. an Indolactam library by Waldmann et al. [11], a Sarcodictyin-based library by Nicoloau et al. [12] and a Taxoid library by Xiao et al. [13]... 

Chart 9 Schematic representation of the principal microtubule stabilizing agents (MSAA) paclitaxel (10) and docetaxel (11), epothilones A-D (12-15), discodermolide (16), eleutherobin (17) and sarcodictyin (18), laulimalide (19) and peloruside A (20)... 

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