RESUMO
Podophyllotoxin, a cyclolignan natural product, has been the object of extensive chemomodulation to obtain better chemotherapeutic agents. Among the obtained podophyllotoxin derivatives, podophyllic aldehyde showed very interesting potency and selectivity against several tumoral cell lines, so it became our lead compound for further modifications, as described in this work, oriented toward the enlargement of the cyclolignan skeleton. Thus, modifications performed at the aldehyde function included nucleophilic addition reactions and the incorporation of the aldehyde carbon into several five-membered rings, such as thiazolidinones and benzo-fused azoles. The synthesized derivatives were evaluated against several types of cancer cells, and although some compounds were cytotoxic at the nanomolar range, most of them were less potent and less selective than the parent compound podophyllic aldehyde, with the most potent being those having the lactone ring of podophyllotoxin. In silico ADME evaluation predicted good druggability for most of them. The results indicate that the γ-lactone ring is important for potency, while the α,ß-unsaturated aldehyde is necessary to induce selectivity in these cyclolignans.
Assuntos
Antineoplásicos , Podofilotoxina , Humanos , Podofilotoxina/farmacologia , Esqueleto , Hipertrofia , Aldeídos , Lactonas , Compostos RadiofarmacêuticosRESUMO
Terpenylquinones are mixed biogenesis primary or secondary metabolites widespread in Nature with many biological activities, including the antineoplastic cytotoxicity, that have inspired this work. Here, we present a cytotoxic structure-activity relationship of several diterpenylhydroquinone (DTHQ) derivatives, obtained from the natural labdane diterpenoid myrceocommunic acid used as starting material. Different structural modifications, that changed the functionality and stereochemistry of the decalin, have been implemented on the bicyclic core through epoxidation, ozonolysis or decarboxylation, and through induction of biomimetic breaks and rearrangements of the diterpene skeleton. All the isomers generated were completely characterized by spectroscopic procedures. The resulting compounds have been tested in vitro on cultured cancer cells, showing their relevant antineoplastic cytotoxicity, with GI50 values in the µM and sub-µM range. The rearranged compound 8 showed the best cytotoxic results, with GI50 at the submicromolar range, retaining the cytotoxicity level of the parent compounds. In this report, the versatility of the labdane skeleton for chemical transformation and the interest to continue using structural modifications to obtain new bioactive compounds are demonstrated.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Proliferação de Células , Diterpenos/química , Hidroquinonas/química , Neoplasias/tratamento farmacológico , Humanos , Estrutura Molecular , Neoplasias/patologia , Células Tumorais CultivadasRESUMO
A new family of molecular hybrids, between cyclolignans related to podophyllic aldehyde and several diterpenylnaphthohydroquinones (DNHQ), was prepared and its biological activity evaluated in several human solid tumor cell lines, which are representative of the most prevalent solid tumors in the Western world. Both cyclolignan and quinone fragments were linked through aliphatic or aromatic spacers. The new hybrid family was evaluated for its cytotoxicity, and it was found that the hybrids were several times more potent against the osteosarcoma cell line MG-63 than against MCF-7 and HT-29 cell lines. The presence of an aromatic ring in the linker gave the most potent and selective agent, improving the cytotoxicity of the parent compounds. Cell cycle studies demonstrated that this hybrid induces a strong and rapid apoptotic effect and arrests cells at the G2/M phase of the cell cycle, in the same way that the parent compound podophyllic aldehyde does.
RESUMO
We report on the synthesis of two series of 1,4-naphthohydroquinone derivatives conjugated with amino acids (Gly, Ala, Phe, and Glu) and with substituted purines linked by an aliphatic chain. The compounds were obtained through Diels-Alder cycloaddition between myrcene and 1,4-benzoquinone and evaluated in vitro for their cytotoxicity (GI50 ) against cultured human cancer cells of A-549 lung carcinoma, HT-29 colon adenocarcinoma, and MCF-7 breast carcinoma. The GI50 values found for some hydroquinone-amino acid and hydroquinone-purine hybrids against MCF-7 are in an activity range comparable to that of the reference drug doxorubicin.
Assuntos
Aminoácidos/síntese química , Aminoácidos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Hidroquinonas/síntese química , Hidroquinonas/farmacologia , Purinas/síntese química , Purinas/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/farmacologia , Células HT29 , Humanos , Concentração Inibidora 50 , Células MCF-7 , Estrutura MolecularRESUMO
This paper reports on the syntheses and spectrometric characterisation of eleven novel ent-kaurane diterpenoids, including a complete set of (1)H, (13)C NMR and crystallographic data for two novel ent-kaurane diepoxides. Moreover, the antineoplastic cytotoxicity for kaurenoic acid and the majority of ent-kaurane derivatives were assessed in vitro against a panel of fourteen cancer cell lines, of which allylic alcohols were shown to be the most active compounds. The good in vitro antimalarial activity and the higher selectivity index values observed for some ent-kaurane epoxides against the chloroquine-resistant W2 clone of Plasmodium falciparum indicate that this class of natural products may provide new hits for the development of antimalarial drugs.
Assuntos
Antimaláricos/farmacologia , Antineoplásicos/farmacologia , Diterpenos do Tipo Caurano/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Antimaláricos/síntese química , Antimaláricos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Morte Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Diterpenos do Tipo Caurano/síntese química , Diterpenos do Tipo Caurano/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Modelos Moleculares , Estrutura Molecular , Testes de Sensibilidade Parasitária , Relação Estrutura-AtividadeRESUMO
The efficacy of three amino-terpenyl naphthoquinones and the alkaloid liriodenine were examined against tachyzoites and tissues cysts of the RH and EGS strains, respectively. Monolayers of 2C4 fibroblasts infected with tachyzoites of the RH strain were incubated with different concentrations of the compounds for 48 h. Specifically, 7-(4-methyl-3-pentenyl)-2-pyrrolidine-[1,4]-naphthoquinone (QUI-5), 6-(4-methyl-3-pentenyl)-2-pyrrolidine-[1,4]-naphthoquinone (QUI-6), 6-(4-methylpentyl)-2-pyrrolidine-[1,4]-naphthoquinone (QUI-11), and 8 h-benzo[g]-1,3-benzodioxolo[6,5,4-de]quinolin-8-one,9Cl-1,2-methylene dioxiaporfina (liriodenine) inhibited intracellular replication of T. gondii. The IC(50) values obtained for compounds QUI-5 and QUI-6 were 69.35 and 172.81 µM (i.e., 21.4 and 53.4 µg/mL), respectively. The naphthoquinone QUI-11 and liriodenine significantly inhibited intracellular replication of T. gondii. The IC(50) values obtained with these experiments were 0.32 and 0.07 µM (i.e., 0.1 and 0.02 µg/mL), respectively. Compounds QUI-5, QUI-6, QUI-11 and liriodenine demonstrated lower toxicity for 2C4 fibroblasts compared to atovaquone. In addition, cysts isolated from the brains of mice chronically infected with the EGS strain were exposed to the compounds. Infectivity of the cysts after incubation with the compounds was assessed by infection of mice. The data obtained showed that in vitro incubation with QUI-6, QUI-11 and liriodenine inhibited the infectivity of the bradyzoites. This activity was time- and concentration-dependent.
Assuntos
Aporfinas/farmacologia , Coccidiostáticos/farmacologia , Fibroblastos/parasitologia , Naftoquinonas/farmacologia , Toxoplasma/efeitos dos fármacos , Animais , Antimaláricos/química , Antimaláricos/farmacologia , Aporfinas/química , Atovaquona/química , Atovaquona/farmacologia , Células Cultivadas , Coccidiostáticos/química , Feminino , Fibroblastos/efeitos dos fármacos , Prepúcio do Pênis/citologia , Humanos , Concentração Inibidora 50 , Masculino , Camundongos , Naftoquinonas/química , Relação Estrutura-Atividade , Sulfadiazina/química , Sulfadiazina/farmacologia , Toxoplasma/patogenicidade , Toxoplasmose Animal/tratamento farmacológico , Toxoplasmose Animal/parasitologiaRESUMO
Diterpenylquinone/hydroquinone derivatives were prepared through Diels-Alder cycloaddition between natural myrcecommunic acid or its methyl ester and p-benzoquinone (p-BQ), using BF(3).Et(2)O as catalyst or under microwave (Mw) irradiation. Acetyl, methyl and benzyl derivatives of several diterpenylnaphthohydroquinone were prepared from cycloadducts following two basic synthetic strategies, either protection before aromatisation or viceversa. Some of them were further functionalised at the B-ring of the decaline core. Most of the new compounds were evaluated and some of them resulted cytotoxic against several tumour cell lines with IC(50) values under the microM level.
Assuntos
Produtos Biológicos/química , Diterpenos/química , Hidroquinonas/síntese química , Hidroquinonas/toxicidade , Acetilação , Benzeno/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Hidroquinonas/química , Espectroscopia de Ressonância Magnética , Metilação , Estrutura Molecular , Oxirredução , Relação Estrutura-AtividadeRESUMO
A series of podophyllotoxin and podophyllic aldehyde derivatives, lacking the lactone ring and oxidized at C-9 position, has been prepared. The functionalities considered at C-9 were carboxylic acids and several derivatives such as esters, amides, nitriles or anhydrides. The synthesized compounds were cytotoxic at the micromolar level, though less potent and selective than the parent compounds, revealing the influence of the C-9 electrophilic character on the potency and selectivity of these cyclolignans.
Assuntos
Antineoplásicos/síntese química , Podofilotoxina/análogos & derivados , Podofilotoxina/farmacologia , Aldeídos , Animais , Antineoplásicos/farmacologia , Ácidos Carboxílicos , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Podofilotoxina/síntese química , Relação Estrutura-AtividadeRESUMO
A series of new furoterpenyl-1,4-naphtho(anthra)quinones have been prepared via oxidative cyclization of the corresponding 2-hydroxy-3-butenyl-1,4-naphtho(anthra)quinones. Depending on the reaction conditions the 1,2-quinones or the 1,4-quinones were obtained. Several new furo-1,4-anthraquinones were also obtained by condensation of 2,3-dichloroquinones with 1,3-dicarbonyls. The compounds synthesized have been evaluated for their cytotoxicity against neoplastic cell lines, some of them being effective below the micromolar level.
Assuntos
Antineoplásicos/farmacologia , Quinonas/farmacologia , Linhagem Celular , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Espectroscopia de Ressonância Magnética , Espectrometria de Massas de Bombardeamento Rápido de ÁtomosRESUMO
Several 2-arylamino-, 2-aryloxy- and 2-arylsulfanyl-6(7)-alkyl-1,4-naphthoquinones (NQ) have been prepared and further transformed into the corresponding heterocyclic-fused naphthoquinones by palladium (II)-catalyzed oxidative cyclization. The compounds synthesized have been evaluated against neoplastic cell lines. The extension of the polycyclic system clearly decreased the cytotoxic potency of the 2-substituted terpenylnaphthoquinones.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Naftoquinonas/síntese química , Naftoquinonas/farmacologia , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Espectroscopia de Ressonância Magnética , Espectrometria de Massas de Bombardeamento Rápido de ÁtomosRESUMO
Several 6(7)-alkyl-1,4-naphthoquinones (NQ) have been prepared by cycloaddition reactions between the monoterpene alpha-myrcene and p-benzoquinones and halogen and nitrogen-containing functional groups have been introduced at the C-2 position of the naphthoquinone ring via nucleophilic addition or substitution reactions. These substituents at positions 2/3 of the NQ clearly influence the cytotoxic potency of this type of compound. Of particular interest is substitution by arylamino, specifically p-oxyarylamino, groups, which considerably enhance their bioactivity and selectivity.
Assuntos
Quinonas/síntese química , Terpenos/química , Espectroscopia de Ressonância Magnética , Quinonas/toxicidade , Espectrofotometria InfravermelhoRESUMO
Several podophyllotoxin derivatives modified in the E-ring were prepared and evaluated for their cytotoxicity on four neoplastic cell lines (P-388, A-549, HT-29 and MEL-28) and for their antiherpetic activity against Herpes simplex virus type II. The trimethoxyphenyl moiety was oxidized to ortho-quinone and further condensed with diamines and enamines to form different heterocycles. Most of the compounds maintained their cytotoxicity at the muM level and some of them showed antiherpetic activity.
Assuntos
Antivirais/síntese química , Podofilotoxina/análogos & derivados , Podofilotoxina/farmacologia , Animais , Antivirais/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Herpesvirus Humano 2/efeitos dos fármacos , Humanos , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Podofilotoxina/síntese química , Relação Estrutura-Atividade , Células VeroRESUMO
Various Diels Alder cycloaddition conditions have been used to optimise the preparation of cytotoxic 6-alkyl-1, 4-naphthoquinones, which were subsequently transformed into 6(7)-alkyl-2-hydroxy-1, 4-naphthoquinones. The compounds thus prepared were evaluated for their cytotoxic activity against several neoplastic cultured cell lines and some of them showed IC50 values below the microM level.