Lignopurines: A new family of hybrids between cyclolignans and purines. Synthesis and biological evaluation

Castro, M. Angeles; Corral, José M. Miguel del; García, Pablo A.; Rojo, María Victoria; Bento, Ana C.; Mollinedo, Faustino; Francesch, Andrés; Feliciano, Arturo San

doi:10.1016/j.ejmech.2012.10.026

Cited by 18 publications

(23 citation statements)

References 48 publications

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“…In our previous synthesized compounds, the cytotoxic hybrids derived from podophyllic aldehyde were synthesized with the linkers attached to the cyclolignan at C-9′ position through ester-type bonds ( Figure 1 ) [ 12 , 13 ]. In those previous works, an improvement in the potency and selectivity was observed for several imino derivatives of podophyllic aldehyde, which also act as inhibitors of the tubulin polymerization.…”

Section: Resultsmentioning

confidence: 99%

“…It shares the same mechanism of action as podophyllotoxin. Recent chemical approaches performed in our group allowed us to prepare new conjugates or hybrids with other types of natural products (i.e., purines and terpenylquinones) ( Figure 1 ), modulating the selectivity of the podophyllotoxin moiety [ 12 , 13 ]. Molecular conjugation or hybridization, as a tool in drug discovery, allows known compounds to improve their pharmacokinetic and pharmacological properties in an easy way.…”

Section: Introductionmentioning

confidence: 99%

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A Novel Cytotoxic Conjugate Derived from the Natural Product Podophyllotoxin as a Direct-Target Protein Dual Inhibitor

et al. 2020

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Natural products are the ideal basis for the design of novel efficient molecular entities. Podophyllotoxin, a naturally occurring cyclolignan, is an example of natural product which displays a high versatility from a biological activity point of view. Based on its unique chemical structure, different derivatives have been synthesized presenting the original antitumoral properties associated with the compound, i.e., the tubulin polymerization inhibition and arising anti-topoisomerase II activity from structural modifications on the cyclolignan skeleton. In this report, we present a novel conjugate or hybrid which chemically combines both biological activities in one single molecule. Chemical design has been planned based in our lead compound, podophyllic aldehyde, as an inhibitor of tubulin polymerization, and in etoposide, an approved antitumoral drug targeting topoisomerase II. The cytotoxicity and selectivity of the novel synthetized hybrid has been evaluated in several cell lines of different solid tumors. In addition, these dual functional effects of the novel compound have been also evaluated by molecular docking approaches.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A Novel Cytotoxic Conjugate Derived from the Natural Product Podophyllotoxin as a Direct-Target Protein Dual Inhibitor

et al. 2020

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“…1) and the derivatives evaluated in this work are compiled in Table 1, Table 2, Table 3, Table 4. Compounds were prepared according to previous reports (Castro et al., 2004, Castro et al., 2010, Castro et al., 2012, Abad et al., 2012) and to unpublished procedures (chemical data not shown here). Their structures were respectively confirmed or assigned by either direct comparison with authentic samples, or through complete analysis of One- and Two-Dimensional 1 H and 13 C nuclear magnetic resonance (1D- and 2D-NMR, respectively), infrared (IR) and mass (MS) spectra for the new compounds.…”

Section: Methodsmentioning

confidence: 99%

Antileishmanial activity and tubulin polymerization inhibition of podophyllotoxin derivatives on Leishmania infantum

Escudero-Martínez

Pérez-Pertejo

Reguera

et al. 2017

International Journal for Parasitology: Drugs and Drug Resistan

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Leishmania microtubules play an important role not only in cell division, but also in keeping the shape of the parasite and motility of its free-living stages. Microtubules result from the self-assembly of alpha and beta tubulins, two phylogenetically conserved and very abundant eukaryotic proteins in kinetoplastids. The colchicine binding domain has inspired the discovery and development of several drugs currently in clinical use against parasites. However, this domain is less conserved in kinetoplastids and may be selectively targeted by new compounds. This report shows the antileishmanial effect of several series of compounds (53), derived from podophyllotoxin (a natural cyclolignan isolated from rhizomes of Podophyllum spp.) and podophyllic aldehyde, on a transgenic, fluorescence-emitting strain of Leishmania infantum. These compounds were tested on both promastigotes and amastigote-infected mouse splenocytes, and in mammalian – mouse non-infected splenocytes and liver HepG2 cells – in order to determine selective indexes of the drugs. Results obtained with podophyllotoxin derivatives showed that the hydroxyl group at position C-7α was a structural requisite to kill the parasites. On regards podophyllic aldehyde, derivatives with C9-aldehyde group integrated into a bicyclic heterostructure displayed more potent antileishmanial effects and were relatively safe for host cells. Docking studies of podophyllotoxin and podophyllic aldehyde derivatives showed that these compounds share a similar pattern of interaction at the colchicine site of Leishmania tubulin, thus pointing to a common mechanism of action. However, the results obtained suggested that despite tubulin is a remarkable target against leishmaniasis, there is a poor correlation between inhibition of tubulin polymerization and antileishmanial effect of many of the compounds tested, fact that points to alternative pathways to kill the parasites.

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“…In general, the reaction products were mixtures of alkylpurines, in which the major regioisomer was the corresponding 9-alkylated product (isomer "a"). In most of the cases, the minor regioisomer, 7-alkylated purine (isomer "b"), was also separated by chromatographic procedures (Scheme 2, entries [1][2][3][4][5][6][7][8][9]. When the diterpenyl bromide 4 was used (entries 16-19), not only isomers "a" and "b" were detected but also the 3-alkylated products (isomers "c") were isolated and even the Z and E stereoisomers were also separated and characterized on the bases of the chemical shi (d) observed in 13 C NMR spectra for the C-16 0 methyl group on the terpenyl moiety.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and cytotoxic evaluation of new terpenylpurines

et al. 2016

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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...

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Lignopurines: A new family of hybrids between cyclolignans and purines. Synthesis and biological evaluation

Cited by 18 publications

References 48 publications

A Novel Cytotoxic Conjugate Derived from the Natural Product Podophyllotoxin as a Direct-Target Protein Dual Inhibitor

A Novel Cytotoxic Conjugate Derived from the Natural Product Podophyllotoxin as a Direct-Target Protein Dual Inhibitor

Antileishmanial activity and tubulin polymerization inhibition of podophyllotoxin derivatives on Leishmania infantum

Synthesis and cytotoxic evaluation of new terpenylpurines

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