Synthesis and cytotoxic evaluation of new terpenylpurines

Abstract

Several new terpenylpurine derivatives were prepared through alkylation of different purines with halogenated reagents derived from natural terpenoids, commercially available or isolated from cones of C. sempervirens L. and further transformed into appropriate alkylated agents. Alkylation of the purines gave mixtures of 9-and 7-alkylpurines, being the 9-alkylpurines the major regioisomers. The presence of the terpenyl residue induced cytotoxicity on simple purines and, in general, that activity improved as the substituent was larger. The 7-diterpenyl-6-chloropurine E-21b was the most cytotoxic in the series and it can be considered an analogue of the marine natural compounds agelasines and agelasimines, which were taken as models for this work. PAPER structure-activity relationship studies, 3 prompted us to design and prepare new terpenylpurine derivatives starting from natural monoterpenoids and diterpenoids, either commercially available or isolated by us from their natural sources, and to evaluate the inuence of the terpenoid size on their cytotoxic properties. Results and discussion ChemistryThe N-alkylpurines described in this work have been prepared by the classical procedure of alkylation of purines with alkyl halides. 9 As starting materials for the synthesis of terpenyl bromides we used the commercial monoterpenoid myrtenal and the diterpenoids trans-communic and cupressic acids isolated from their natural sources. We also used other commercially available alkyl halides such as 1-bromopentane, cynnamyl bromide, isoprenyl chloride and geranyl bromide.Myrtenal was easily transformed into the myrtenyl bromide 1 through NaBH 4 reduction followed by substitution of the hydroxyl group with CBr 4 , 10 in this way, compound 1 was obtained in 87% overall yield from myrtenal (Scheme 1). trans-Communic and cupressic acids were isolated from the acid fraction of the n-hexane extract of Cupressus sempervirens L. cones (Cupressaceae). Both acids were quantitatively transformed into their corresponding methyl esters by treatment with trimethylsilyldiazomethane 11 and then transformed into the terpenyl bromides 3, 3 0 and 4 as shown in Scheme 1. Epoxidation of the trisubstituted double bond in methyl transcommunate, followed by oxidation with periodic acid 12 yielded the tetranorditerpenic aldehyde 2, which was transformed into the bromide 3 by reduction and substitution as described for myrtenal. Bromide 3 0 was prepared following the same procedure, previous isomerization of the exocyclic double bond. 6b Diterpenyl bromide 4 was obtained in 77% yield by treatment of methyl cupressate with PBr 3 at À35 C. 13 Nucleophilic substitution and allylic isomerization took place at once and compound 4 was obtained as an unresoluble mixture of the E and Z isomers in a 5 : 1 ratio that was used for the alkylation step. Fig. 1 Chemical structure of several natural alkylpurines. Scheme 1 Preparation of the bromo-derivatives, used as electrophiles, from natural terpenoids. This journal is RSC Advances Paper a GI 50 values are expre...

Screening for Small Molecule Modulators of Trypanosoma brucei Hsp70 Chaperone Activity Based upon Alcyonarian Coral-Derived Natural Products

“…Other readily available N-heterocyclic compounds were also alkylated, including the pyrimidines, uracil (51), thymine (52), and cytosine (53). Alkylation of 51, and 52 yielded only N-1 monoalkylated derivatives (54)(55)(56)(57)(58)(59) whereas 53 only produced N-1,N-3 dialkylated products (61, 63) (Scheme 6). In addition to the dialkylated cytosines, formylated imine derivatives (60,62,64) were also isolated, likely formed via the reaction solvent, DMF.…”

Marine Alkylpurines: A Promising Group of Bioactive Marine Natural Products

“…A series of new neutral 9- and 7-terpenylpurines have been prepared by Castro et al with monoterpenoid, sesquiterpenoid and diterpenoid side chains using commercial monoterpenoids such as myrtenal or geranylbromide and diterpenoids such as trans -communic acid (degradation of the side chain gave the sesquiterpenoid moiety) and cupressic acid isolated from their natural sources ( Scheme 6 ) [ 138 ]. The cytotoxic evaluation against several human tumour cell lines indicated that the terpenyl chain induced cytotoxicity on simple purines, and this activity was higher as larger was the substituent, i.e., the best results were shown by the diterpenylpurines, in some cases with a very interesting low toxicity for non-tumour cells [ 138 ].…”