Camptothecin, irradiation

In a similar way (and as described for the aromatic isocyanides), aliphatic a, 3-un-saturated isocyanides can also be used, leading to similar structures with a cyclo-hexano instead of a benzo moiety [84]. Based on the approach using aromatic isocyanides, a small library of about 20 camptothecin derivatives has been prepared, of which irinotecan and topotecan have entered the clinical treatment of cancer [85]. For the synthesis of the camptothecin derivatives, 3-206 was alkylated with the appropriate propargylic bromides 3-207 to give 3-208, which were irradiated in benzene at 70 °C, together with the respective isocyanide 3-209 and hexamethylditin... 

Das has described the cycloaddition of camptothecin (92), an alkaloid with potent antitumor activity, with maleic anhydride under the action of microwave irradiation in a commercial microwave oven for 9 min [78]. Two unprecedented adducts, 93 and 94, were produced. The first was formed by involvement of the B-ring in a hetero Diels-Alder reaction whereas the second was formed by involvement of the C-ring, probably through Diels-Alder reaction of intermediate 95 (Scheme 9.28). 

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

The rationale for combining 9-AC with irradiation was based on in vitro work with human colon and pancreatic cancer cell lines showing dose dependency for cytotoxicity and radiation sensitization and other reports that it is a potent radiation sensitizer in vivo (21). Unfortunately, this agent is not very well tolerated in man and clinical studies have been abandoned (12). Another agent is 9-nitro-camptothecin that is converted into 9-AC in vivo, which has also been shown to be active in vitro and in vivo (44,45). 

Kirichenko AV, Mason K, Straume M, Teates CD, Rich TA. Nuclear scintigraphic assessment of intestinal dysfunction after combined treatment with 9-amino-20(S)-camptothecin (9-AC) and irradiation. Int JRadiat Oncol Biol Phys 2000 47(4) 1043-1049. 

The Indian tree Nothapodytes foetida (syn. Mappia foetida) is an important source of camptothecin, the DNA topoisomerase I inhibitor possessing anti-cancer and anti-HIV activity of significant therapeutic importance. One of the minor components of the plant has been identified as 9-methoxy-20-(S)-mappicine, a tetracyclic derivative of the pentacyclic camptothecin. When the latter compound was treated for a short-time (7 min) with microwave irradiation, it was converted into 9-methoxymappicine ketone with an exceptionally high yield of 95%. This ketone was then easily transformed by baker s yeast into the target compound 9-methoxy-20-(S)-mappicine as illustrated in Fig. 15 [91]. 

Camptothecin was irradiated under solvent-free conditions for 7 min at the full power of the microwave oven (Scheme 28). The product, Mappicine ketone, was isolated in 96% yield without a trace of undesired side products, which clearly exhibits the potential of microwave-assisted chemistry. In comparison, when the reaction was run at rt in THF and in the presence of BF3 x Et20, Mappicine ketone was isolated in a mere 65% yield. 

A naturally occurring pyrrolo[3,4-Z)]quinoline alkaloid 415, named camptothecin, has a promising antineoplastic activity in animal tumor models. When 415 was irradiated with MW under solvent-free conditions, it gave mappicine ketone 416 in 96% yield within 7 min (Scheme 83) 416 was found to be an antiviral lead compound. Under conventional conditions, 415 reacted with borontrifluoride etherate in THF at room temperature for 1.5 h to give 416 in 65% yield (98TL431). 

In 1992, novel methodology for the construction of the camptothecin molecule was reported by Curran et al [57-59]. They have applied a novel (4 + 1) radical annulation reaction to the construction of rings B and C of camptothecin. Reaction of A-propargylpyridone (11) with phenyl isonitrile and hexamethylditin under irradiation with a sunlamp gave the tetracyclic compound (12), which was readily converted to (20RS)-camptothecin (13) (Scheme 2.1) using Danishefsky s procedure [60]. The synthesis of key com-... 

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