Potent antitumor agent

A combination of Cp nCX —A CXC) (where = cyclopentadienyl) effectively promotes the Friedel-Crafts coupling of glycosyl fluorides with aromatic compounds, such as trimethoxyben2ene or methoxynaphthalenes. The derived C-aryl glycosides are potent antitumor agents (39). 

Many notable examples of the synthesis of complex natural products from optically pure starting materials have been reported (70). One synthesis of considerable interest is that of taxol [33069-62-4] (74), a potent antitumor agent used clinically. The starting material (73) used ia the first total synthesis of taxol is produced ia enantiomericaHy pure form from inexpensive and readily available /-camphor [464-48-2] (72) (73). 

The first synthesis of the potent antitumor agent maytansine was carried out by the elaboration of aldehyde D, an intermediate in the enantioselective synthesis of (-)-A/-methylmaysenine (Ref. 1,2), using enantioselective and diastereoselective steps. 

An early example of cyclopentene-opening/double RCM leading to bis-dihy-dropyran 380 (the C22-C34 segment of the potent antitumor agent halichondrin A) was disclosed by Burke et al. (Scheme 74) [158]. In this case, the ROM-RCM sequence was performed with catalyst B, leading from cyclopentene 379 to 380 in 71% yield. When metathesis precursor 379 was exposed to catalyst A, only one... 

There are numerous examples of intramolecular Heck reactions,151 such as in Entries 10 to 14. Entry 11 is part of a synthesis of the antitumor agent camptothecin. The Heck reaction gives an 11 1 endocyclic-exocyclic mixture. Entries 12-14 are also steps in syntheses of biologically active substances. Entry 12 is part of a synthesis of maritidine, an alkaloid with cytotoxic properties the reaction in Entry 13 is on a route to galanthamine, a potential candidate for treatment of Alzheimer s disease and Entry 14 is a key step in the synthesis of a potent antitumor agent isolated from a marine organism. 

Zheng G, Lu W, Aisa H A and Cai J (1999), Absolute configuration of falcarinol, a potent antitumor agent commonly occurring in plants , Tetrahedron Lett, 40, 2181— 2182. 

Although N-methyl-N-nitrosourea can induce cancer in human beings, its derivatives were found to be potent antitumor agents. l,3-Bis(2-chloroethyl)-l-nitrosourea (BCNU), l-(2-chloroethyl)-3-cyclohexyl-l-nitrosourea (CCNU) and l-(2-chloroethyl)-3-(2,6-dioxo-3-piperidyl-l-nitrosourea (PCNU) l-(2-Choroethyl)-3-(4-methylcyclo-hexyl)-l-nitrosourea and l-(2-chloroethyl)-3-cyclohexyl-l-nitrosourea showed antitumor activity by alkylating with DNA [82-84]. N-Nitrosourea-based prodrugs designed to become activated by tumor-associated proteases were found to provide enhanced... 

Isocyanide-based MCR was also applied for the total synthesis studies of natural products containing piperazine substructure. For example, trabectedin (also known as ecteinascidin 743 or ET-743) is undergoing clinical trials for the treatment of breast, prostate, and pediatric sarcomas. Ecteinascidin 743 (2) is an extremely potent antitumor agent isolated from a marine tunicate, Ecteinascidia turbinate [12]. Eukuyama et al. developed the total synthesis of ecteinascidin 743 from a Ugi reaction [13]. The reaction of p-methoxyphenyl isocyanide 3 gave Ugi product 7, which was cyclized to DKP intermediate 8 (Scheme 1). 

Rinehart KL, Holt TG, Fiegeau NL, Stroh JG, Keifer PA, Sun F, Li LH, Martin DG (2002) Ecteinascidins 729, 743, 745, 759A, 759B, and 770 potent antitumor agents from the Caribbean tunicate Ecteinascidia turbinata. J Org Chem 55(15) 4512-4515... 

The actinomycins, which are also produced by Streptomyces, not only kill bacteria but also are among the most potent antitumor agents known.b However, because of their extreme toxicity they are of little medicinal value. Actinomycin D, which is a specific inhibitor of RNA polymerase, contains a planar phenoxazone chromophore bearing two carboxyl groups, each one linked to an identical cyclic peptide made up of L-threonine, D-valine, L-proline, sarcosine (N-methylglycine), and L-methylvaline. 

Transformation of o-methoxyphenol (135) into o-quinone monoacetal (136) using PIDA was used for the initial step of the synthesis of the enediyne aglycone, ( )-calicheamicinone (10), of the potent antitumor agent calicheamicin [93] (Scheme 10). 

Daunomycin and its analog adriamycin are in clinical use as potent antitumor agents in combination chemotherapy against acute lymphocytic leukemia. It has been suggested that the antitumor properties are associated with intercalation of the anthracycline ring of the antibiotic into the DNA of rapidly proliferating neoplastic cells and subsequent blocking of RNA synthesis (72-75). [5]... 

Salicylihalamides/Oximidines Potent Antitumor Agents with Selective anti-V-ATPase Activity... 

Another, albeit less-frequently employed option for a copper-mediated reduction of propargylic electrophiles to allenes relies upon the use of a copper hydride, for example, Stryker s reagent [(Ph3P)CuH]6. This reagent was applied by Brummond and Lu147 to the synthesis of the structurally complex precursor 197 for a potent antitumor agent, ( )-hydroxymethylacylfulvalene, from propargyl acetate 196 (Equation (11)). 

In the first synthesis of the potent antitumor agent may famine 131) by Corey et al. [75], linear amino acid 129 was first converted to the soluble tetra-n-butylammonium salt and then slowly added to a solution of excess mesitylene-sulfonyl chloride and diisopropylethylamine in benzene at 40 °C for 28 h to afford macrolactam 130 in 71% yield (Scheme 44). 

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