Calyculin derivative

Following the first report of tumor promotion by okadaic acid, additional tumor promoters of the okadaic acid activity class have been identified, e.g., microcystin [513,514], and calyculin derivatives, Fig. (63) reported in marine sponges such as Discodermia calyx [515] and Theonella swinhoei [516] as potent inhibitors of tumor cell proliferation. A two-sponge association, Poecillastra sp. and Jaspis sp., yielded cytotoxic toxins which exhibited selective activity against several tumoral cell lines [517],... 

Further examination of D. calyx led to the isolation of calyculin J (102), whose structure was confirmed by chemical transformation from calyculin A (100) [111] and four more calyculin derivatives,... 

Edrada, R.A., Ebel, R., Supriyono, A., Wray, V., Schupp, P., Steube, K., Van Soest, R, and Proksch, P. (2002a) Swinhoeiamide A, a new highly active calyculin derivative from the marine sponge Theondla swinhoei.]. Nat. Prod., 65, 1168-1172. 

The selective intramolecular nucleophilic addition of a hydroxy group at Cyof a ruthenium allenylidene generated by activation of propargylic alcohol by RuCl(Cp)(PPh3)2/NH4PF6 provides a ruthenium vinylidene species, which reacts with allylic alcohols as previously described in the section Formation of Unsaturated Ketones (Eq. 11, Scheme 18) [79]. This unprecedented tandem reaction makes possible the construction of tetrahydrofuran derivatives in good yields and has been used as a key step in the synthesis of (-)calyculin A [80]. 

Model studies aimed at the synthesis of Calyculin discovered a subtle effect of a remote protecting group on the stereoselectivity of an epoxidation reaction [Scheme 1,46], 79 Treatment of the unprotected diol derivative 46.1 with potassium carbonate, benzonitrile and hydrogen peroxide gave a diastereoisomeric mixture of epoxides 46.2a,b (3 1) in favour of 46.2a. However, the same reaction performed on the terf-butyldiphenylsilyl ether 463 both increased the selectivity (1 18) and inverted its sense now 46 4b was the major product. 

The C33-C37-unit of (-F)-calyculin A (a marine natural product) is an amide derived from 5-0-methyl-4-deoxy-4-dimethylamino-D-ribonic acid, which has been prepared by Evans and... 

Tautomycin was obtained from the terrestrial microorganism Streptomyces spiroverticillatus and is chemically characterised as an ester of a carboxylic acid derived fi om a dialkyl maleic anhydride, with a long chain (26-C) polyol containing two cyclic ethers. In a simultaneous study of the best-known natural inhibitory compounds of PP2A, in which the non-radioactive malachite green assay was applied, tautomycin was the least potent compound [144]. This is consistent with the findings reported by Honkanen et al. [129] and other authors. Its primary site of phosphatase inhibition is PPlc, as was reported in a comparative study with okadaic acid and calyculin A [131]. 

The C33-C37-unit of (-F)-calyculin A (a marine natural product) is an amide derived from 5-0-methyl-4-deoxy-4-dimethylamino-D-ribonic acid that has been prepared by Evans and co-workers [250]. A-Protection of sarcosine as benzyl carbamate affords acid 118 which is activated and used to iV-acylate the (5)-phenylalanine-derived oxazolidinone. This gives 119 that is methoxymethylated diastereoselectively (98 2) to give 120. Reductive removal of the chiral auxiliary, followed by Swem oxidation forms aldehyde 121 with little racemization if... 

Microcystin-LR (and derivatives), Calyculin A, Tautomycin, and Nodularin are nonspecific PP2A inhibitors, which retain significant potential to inhibit PPl as well (Table 3). 

Recently, Lazo and co-workers reported a combinatorial library of PTPIB inhibitors based on a pharmacophore derived from the structure-activity relationships for several natural product inhibitors of PSTPases such as oka-daic acid, microcystins and calyculin A [425, 426], The pharmacophore model involved a carboxylate, a non polar aromatic group and hydrogen-bond acceptors and donors and was used as a platform for functional group variation. Among the 18 library compounds generated by parallel solid-phase chemistry, a non-competitive inhibitor for PTPIB was identified (library 41, Kj=0.85 jiM) [425] and as well a serine/threonine phosphatase inhibitor (library 42, IC50 < 100 /iM) [426],... 

Total syntheses of (-l-)-calycuhn A and (—)-calyculin B from the ribonolactone derivative have been reported (Schemes 6 and Compound 44 was coupled with amine 45 to afford... 

Synthesis of 7 -amino acid-oxazole fragment 68 of calyculins A and B from D-erythronol-actone 58 has been reported by conversion to 59," which was subjected to oxidation reaction to afford the hemiaminal 60 (Scheme 9) Acetylation of 60 furnished 61, which was converted to ketone 62 in 88% yield. Conversion of 62 to a silyl enol ether, ozonolysis with reductive workup and O-methylation of the resultant alcohol 63 furnished 7 -lactam 64. Treatment of 64 with CAN led to 65 (60%), which was reacted with (CHj)2 A1 derivative of 66 to provide 67 (62%), which upon removal of the silyl group provided 68. 

The oxazole derivative 237 is a key component for the synthesis of cell permeable phosphatase inhibitors calyculins A and B and it is prepared via coupling of alkylamino oxazole 235 and -/V-protected acid 236.87... 

Malic acid-derived ( S)-pantolactone (257) has been used as a starting point for the stereoselective construction of the C-14 to C-25 spiroketal subunit of calyculin (Scheme 35) [87]. 

In one case, a Wacker oxidation of an olefin to form a ketone was used to prepare fragments for the synthesis of Calyculins. The ketone was then converted via the vinyl tri-flate to the vinyl bromide. In a second example, Wacker oxidation was used in the synthesis of a taxol derivative. In this case, the Wacker oxidation of an olefin was conducted at the later stage of a synthesis. Oxidation of a pendant olefin formed a ketone, which cyclized by condensation with a second keto fimctionality. 

Related to the incorporation of known pharmacophores into libraries, are those libraries utilizing biologically active natural products as design anchors. Library 2.6, based on the protein phosphatase inhibitor, calyculin-A, and library 4.10, derived from the antibacterial, neomycin B, illustrate this strategy. 

Siliquariaspongia°, Theonella Macrolactones, atypical sterols, linear and cyclic peptides, cyclic depsipeptides, nitrogen-containing sesquiterpenes, pyridine derivatives, acetylenic derivatives, phosphorus derivatives analogues of calyculin, tetramic acid glycosides... 

Kabeya, M., Hamada, Y, and Shioiri, T. (1997) Synthesis of y-lactone derivatives as a key intermediate for the spiroketal fragment in calyculin A. Tetrahedron, 53, 9769-9776. 

---