The formation of 2 photochemically from 1 could be thought of in terms of a concerted ["2a + T2a] cycloaddition reaction;11 however, such a mechanism does not account for the formation of 3.15 An alternative pathway, which can account for the production of both 2 and 3, is an electrocyclic ring-opening reaction that breaks the CeC7 bond of 1 to give the open-chain cation 12. Such a process is directly comparable to that observed upon the photoisomerization of the isoelectronic cyclohexa-1,3-dienes to the bicyclo[3.1.0]hexenes.1116 While the direct isomerization of 12 to give 2 is possible, in view of the constant ratio of 2 to 3 observed in these reactions, it is attractive to consider that a cation resembling 11 might be formed either photochemically, or thermally, from 12 and that this gives the observed products, 2 and 3.(15) A trans ring juncture would result from the alternative [
Two pentacyclic triterpenes isolated from Maprounea africana, 1ßhydroxymaprounic acid 3-/>-hydroxybenzoate [3], 2a-hydroxymaprounic acid 2,3-bis-phydroxybenzoate [4] and their respective hydrolyzed products [5] and [6], have been found to demonstrate potent inhibitory activity against HIV-1 reverse transcriptase.
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 (CPT) analogs that form more stable ternary complexes with DNA and topoisomerase I (termed cleavable complexes) show greater activity in their ability to inhibit tumor cell line growth in preclinical studies. Based on our earlier work, we hypothesized that analogs bearing hydrogen bonding moieties at the 7-through 10-position of CPT would result in more stable cleavable complexes. Consequently, we synthesized analogs with 7-mono-, 7-di-, and 7-trihydroxymethylaminomethyl groups. These analogs showed increasing cleavable complex stability as the number of hydroxyl groups was increased. The 7-trihydroxymethylaminomethyl analog of 10,11-methylenedioxycamptothecin (THMAM-MD) showed remarkable ternary complex stability with a half-life of 116 minutes. This is an order of magnitude more stable than any previously examined analog. Our in vitro analysis demonstrated that these analogs were all potent topoisomerase I poisons and could inhibit tumor cell growth in culture. We studied the effects of THMAM-MD in vivo in severe combined immunodeficient mice bearing HT-29 colon cancer and MiaPaCa-2 pancreatic cancer tumors. The THMAM-MD analog showed excellent, persisting activity in inhibiting tumor growth with both lines. Taken together, our results suggest that CPTs with hydrophilic, hydrogenbonding groups at the 7-position hold the promise of excellent clinical activity.
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