Plant antitumor agents. II. Structure of two new alkaloids from Camptotheca acuminata

Abstract

Further fractionation of C. acuminda has yielded two new alkaloids, hydroxycamptothecin (2) and methoxycamptothecin (3). The former could be methylated to give a methyl ether identical with 3. In order to establish the position of the hydroxyl group in ring A, MU spectra of deuterated methoxycamptothecin and of the model compounds 7-10 have been obtained. The syntheses of model compounds have been described.The isolation and structure of camptothecin 1, an alkaloid with a novel ring system exhibiting potent antileukemic and antitumor activities, has been reported from our laboratory.* Further fractionation of C. acuminata has resulted in the isolation of two minor and related components hydroxycamptothecin (2) and methoxycamptothecin (3) both possessing good antileukemic activity in L-1210 (Chart I*). This report is on the characterization of these two alkaloids. CHART I 1,Ri = OH; RI = H 2, Ri = Fb = OH 3, RI = OH; R, 4, Ri = OH; R, 5, RI = Ik = OnCCH, OCHi OsCCHsThe molecular composition of 2 (CaJ€~sNtOs) as determined by mass spectrometry suggested that it might be a monohydroxy derivative of 1 (C&1sNaOd). This hypothesis waa further supported by the formation of mono (4) and diacetate (5) derivatives. The ultraviolet spectra of compounds 4 and 5 were similar to that of 1 thereby suggesting the presence of the same camptothecin chromophore in these compounds. The phenolic nature of the hydroxyl function was evidenced by the positive ferric chloride test and bathochromic shifts in the ultraviolet spectrum of 2 in the presence of dilute base. Treatment of 2 with diazomethane gave a compound identical with 3 obtained from natural sources. Hence, methoxycamptothecin is the methyl ether of hydroxycamptothecin.The phenolic nature of the additional hydroxyl function in 2 meant it could be present in only one of the three rings, A, B, or D. The nmr spectra of 1 and 2 were quite similar except for some differences in the (1) Thb investigation was conducted under Contract SA-43-ph 4322,

Camptothecin and taxol: Discovery to clinic

“…The isolation and structure proof for camptothecin and some of the analogs obtained at an early stage, 10-hydroxy and 10-methoxy camptothecin 12 enabled extensive studies to be conducted on CPT and a few of its analogs. As stated previously, CPT was remarkably active in the life prolongation of mice treated with L1210 leukemia cells, showing activity in doses between 0.5 to 4.0 mg/kg in this L1210 mouse life prolongation assay.…”

“…10-Methoxy-CPT was found to be active but somewhat less active than CPT, whereas 10-hydroxy-CPT was the most active compound in the series and was more active than CPT in both L1210 and P388 leukemia life prolongation assays. [12][13][14] Unfortunately, 10-hydroxy-camptothecin is found in nature in only very small quantities, probably amounting to about 10% of the camptothecin content. All of these previous compounds were extremely insoluble in water, but it will be recalled that the lactone could be opened under mild circumstances with sodium hydroxide or sodium methoxide, and it was found that this sodium salt of CPT was very soluble in water.…”

“…Other reactions also point to the absolute requirement of the ␣-hydroxy group, as shown by the fact that after replacement of this group by chlorine, both the resultant chloroanalog and the corresponding reduction product, desoxycamptothecin, are inactive in L1210 leukemia. 12 Reduction of the lactone under mild conditions to give the lactol also results in complete loss of activity.…”

Dendrimer-Encapsulated Camptothecins: Increased Solubility, Cellular Uptake, and Cellular Retention Affords Enhanced Anticancer Activity In vitro

“…10HCPT was isolated from C. acuminata (44) and BACPT was synthesized as described recently (45). The synthesis of the hydroxylterminated generation four-PGLSA dendrimer, [G4]-PGLSA-OH, was carried out as described in a previous publication (34).…”

Development and validation of a RP-HPLC method with fluorescence detection for simultaneous determination of 10-methoxycamptothecin and its metabolite 10-hydroxycamptothecin in rat plasma

“…1) and 10-methoxycamptothecin (MCPT, Fig. 1) [3], both possessing better activities against the cell line 9KB (human nasopharyngeal carcinoma) in vitro and P388 lymphocytic leukemia system in vivo [4]. The anticancer mechanism of CPTs is based on the inhibition of DNA replication by stabilizing cleavable complexes formed between topoisomerase I and DNA [5].…”