Antitumor agent camptothecin

The Mitsunobu conditions can be used for alkylation of 2-pyridones, as in the course of synthesis of analogs of the antitumor agent camptothecin. 

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. 

The Friedlander reaction is the acid- or base-catalyzed condensation of an ortho-acylaniline with an enolizable aldehyde or ketone. Henichart and coworkers have described microwave-assisted Friedlander reactions for the synthesis of indoli-zino[l,2-b]quinolincs, which constitute the heterocyclic core of camptothecin-type antitumor agents (Scheme 6.238) [421], The process involved the condensation of ortho-aminobenzaldehydcs (or imines) with tetrahydroindolizinediones to form the quinoline structures. Employing 1.25 equivalents of the aldehyde or imine component in acetic acid as solvent provided the desired target compounds in 57-91% yield within 15 min. These transformations were carried out under open-vessel conditions at the reflux temperature of the acetic acid solvent. 

Slichenmyer WJ, Rowinsky EK, Donehower RC, Kaufmann SH. The current status of camptothecin analogues as antitumor agents. J. Natl. Cancer Inst. 1993 Feb 17 85(4) 271-91. 

Camptothecins as Antitumor Agents Clinical Pharmacology of the CPTs Interaction with Irradiation Topotecan Irinotecan... 

Using a modified Minisci reaction, the 4-position of the quinoline ring in alkaloid 195 (camptothecin) was substituted to afford the highly active antitumor agent 196 (karenitecin) (Equation 105) <2001USP6194579>. 

In summary, the development in the field of total syntheses of the antitumor agent camptothecin nicely illustrates the progress of modern synthesis over the last decade. Radical reactions and organometallic coupling reactions, for example, have reached such a level of maturity that they now belong to the standard repertoire of key steps in the construction of complex molecules. 

The discovery of Taxol is a fruit of a National Cancer Institute (NCI)-sponsored project on identification of antitumor agents from natural resources. Bioassay-guided fractionation led to the isolation of this unique compound from Taxus bre-vifolia (pacific yew). Wani et al. also identified another famous antitumor natural product camptothecin. Unlike camptothecin, which was abandoned in the phase of clinical trial because of its severe toxicity, Taxol was almost discarded at the preliminary phase because it only exhibited moderate in vitro activity toward P388, a murine leukemia cell line that was used in the standard evaluation system by NCI researchers at that time. However, it was rescued by a subsequent finding of its strong and selective antitumor activities toward several solid tumors, and more... 

Ohtsu, H. Nakanishi, Y Bastow, K. R Lee, R.-Y Lee, K.-H. Antitumor agents 216. Synthesis and evaluation of paclitaxel-camptothecin conjugates as novel c3dotoxic agents. Bioorg. Med. Chem., 2003, 11 1851-1857. 

Hennenfent KL, Govindan R. Novel formulations of taxanes a review. Old wine in a new bottle Ann. Oncol. 2006 17 735-749. Wall ME, Wani MC, Cook CE, Palmer KH, McPhail AT, Sim GA. Plant antitumor agents. 1. The isolation and structure of camptothecin, a novel alkaloidal leukemia and tumor... 

Bastow KF, Wang HK, Cheng YC, Lee KH. Antitumor agents 59. 173. Synthesis and evaluation of camptothecin-4P-amino-4 -0-demethyl epipodophyllotoxin conjugates as inhibitors of mammalian DNA topoisomerases and as cytotoxic agents. Bioorg. 60. Med. Chem. 1997 5 1481-1488. 

Intermolecular events can also intervene in spectacular radical cascades. Curran used isonitriles as versatile partners for the preparation of eyclopentaquinolines. This was applied to the synthesis of the antitumor agent (20S)-camptothecin (Scheme 3) [4]. 

The potent antitumor agents camptothecin (11) and its derivatives are targets of extensive synthetic activities. [7] A major contribution to this research area came from the laboratory of D. R Curran [3] in Pittsburgh with a total synthesis of camptothecin relying on radical chemistry. In the key step of his synthesis (Scheme 2) the iodoalkyne 9 was allowed to react with phenyl isonitrile to provide the target compound 11. 

Rao and co-workers effected cycloaddition of 8 with the propargylic aldehyde 156 to afford the 2,3,4-trisubstituted furan 157 in 90% yield in their regioselective synthesis of the antitumor agent camptothecin (Fig. 3.47). Several steps were required to convert 157 to the butenolide 158, a key synthon for the D- and E-rings of... 

Wall, M. E., M. C. Wani, C. E. Cook, K. H. Palmer, A. T. McPhail, and G. A. Sims, Plant antitumor agents. I. The isolation and structure of camptothecin, a novel alkaloidal leukemia and tumor inhibitor from Camptotheca acuminata, J. Am. Chem. Soc., 88, 3888-3890 (1966). 

The reaction can be extended to the case in which two alkynes and a nitrile are trimerized to give a pyridine or two alkynes and an isocyanate are tri-merized to give an a-pyridone, also shown in Eq. 14.63, as exemplified in syntheses of vitamin 85, a pyridine derivative, and the antitumor agent, camptothecin, an a-pyridone. 

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