Kinesin motors inhibitor

Utilization of a similar [Sc(OTf)3-promoted)] approach by Overman on the ger-anylgeraniol-derived cyclization substrate 98 provided the desired tetracyclization product 99, in which the terminator of the cationic cyclization is an arene group. Compound 99 is then transformed into the kinesin motor protein inhibitor adocia-sulfate 1 (Scheme 8.27) [47]. 

Bogaistfitter, M. Limb g, A. Overman. L.E. Tmnasi, A.L. (1999) Enantioselective total synthesis of the kinesin motor protein inhibitor adociasulfate I. J. Am. Chem. Soc., 121,12206-7. 

Adociasulfates 1-6 (380-385) were isolated from a Haliclona (aka Adocia) sp. from Palau and were all inhibitors of kinesin motor proteins [331]. Adociasulfate 2 (381) had earlier been shown to inhibit the activity of the motor protein kinesin by interference with its binding to microtubules [332], An Adocia sp. from the Great Barrier Reef contained adociasulfates 1 (380), 7 (386) and 8 (387), which inhibit vacuolar H -ATPase [333]. Adociasulfates 5 (384) and 9 (388) were obtained from Adocia aculeata from the Great Barrier Reef [334], The structure of adociasulfate 1 (380) was confirmed by an enantioselective total synthesis [335]. Adociasulfate 10 (389) from Haliclona sp. from Palau also inhibits the kinesin motor proteins [336]. 

From the marine sponge Haliclona sp. (also known as Adocia sp.), a family of hexaprenoid hydroquinones called adociasulfates, have been recently reported as inhibitors of kinesin motors [100,101], These types of compounds were also found in several soft corals, such as Lemnalia africana [102], Okinawan soft coral of Nephthea sp. [103], and the gorgonian Alertogorgia sp., which yielded the cytotoxic tricyclic sesquiterpene, suberosenone [104],... 

Monastrol Synthehc, idenhhed as cell-division inhibitor (24). Inhibits the kinesin-5 motor protein. 

Figure 1.9 Identification of monastrol (an inhibitor of the normal mitotic spindle formation) and its molecular target (a molecular motor protein, kinesin, Eg5) using chemical genomics.

Monastrol (Figure 10), the most representative Biginelli adduct in anticancer drug development, showed to be a cell permeable molecule whose mechanism of action on cancer cells involves the selective inhibition of kinesin Eg5 [63]. Kinesin Eg5 is a motor enzyme that is responsible for the formation and maintenance of mitotic spindles. The inhibition of this enzyme activity by monastrol leads to the loss of chromosome alignments and bipolar spindle formation. The resulting "monastral phenotype" inspired scientists to name this specific Biginelli compound as monastrol [63]. Fluorastrol (Figure 10), a monastrol-derived Eg5 inhibitor, showed to be more potent... 

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