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1.
Molecules ; 29(7)2024 Mar 23.
Article in English | MEDLINE | ID: mdl-38611722

ABSTRACT

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.


Subject(s)
Antineoplastic Agents , Podophyllotoxin , Humans , Podophyllotoxin/pharmacology , Skeleton , Hypertrophy , Aldehydes , Lactones , Radiopharmaceuticals
2.
Molecules ; 26(2)2021 Jan 18.
Article in English | MEDLINE | ID: mdl-33477484

ABSTRACT

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.


Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Proliferation , Diterpenes/chemistry , Hydroquinones/chemistry , Neoplasms/drug therapy , Humans , Molecular Structure , Neoplasms/pathology , Tumor Cells, Cultured
3.
ACS Med Chem Lett ; 9(4): 328-333, 2018 Apr 12.
Article in English | MEDLINE | ID: mdl-29670695

ABSTRACT

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.

4.
Arch Pharm (Weinheim) ; 346(12): 882-90, 2013 Dec.
Article in English | MEDLINE | ID: mdl-24123148

ABSTRACT

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.


Subject(s)
Amino Acids/chemical synthesis , Amino Acids/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Hydroquinones/chemical synthesis , Hydroquinones/pharmacology , Purines/chemical synthesis , Purines/pharmacology , Cell Survival/drug effects , Doxorubicin/pharmacology , HT29 Cells , Humans , Inhibitory Concentration 50 , MCF-7 Cells , Molecular Structure
5.
Eur J Med Chem ; 62: 168-76, 2013 Apr.
Article in English | MEDLINE | ID: mdl-23353738

ABSTRACT

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.


Subject(s)
Antimalarials/pharmacology , Antineoplastic Agents/pharmacology , Diterpenes, Kaurane/pharmacology , Plasmodium falciparum/drug effects , Antimalarials/chemical synthesis , Antimalarials/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Death/drug effects , Cell Proliferation/drug effects , Diterpenes, Kaurane/chemical synthesis , Diterpenes, Kaurane/chemistry , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Models, Molecular , Molecular Structure , Parasitic Sensitivity Tests , Structure-Activity Relationship
6.
Exp Parasitol ; 132(4): 450-7, 2012 Dec.
Article in English | MEDLINE | ID: mdl-23000485

ABSTRACT

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.


Subject(s)
Aporphines/pharmacology , Coccidiostats/pharmacology , Fibroblasts/parasitology , Naphthoquinones/pharmacology , Toxoplasma/drug effects , Animals , Antimalarials/chemistry , Antimalarials/pharmacology , Aporphines/chemistry , Atovaquone/chemistry , Atovaquone/pharmacology , Cells, Cultured , Coccidiostats/chemistry , Female , Fibroblasts/drug effects , Foreskin/cytology , Humans , Inhibitory Concentration 50 , Male , Mice , Naphthoquinones/chemistry , Structure-Activity Relationship , Sulfadiazine/chemistry , Sulfadiazine/pharmacology , Toxoplasma/pathogenicity , Toxoplasmosis, Animal/drug therapy , Toxoplasmosis, Animal/parasitology
7.
Bioorg Med Chem ; 15(17): 5760-74, 2007 Sep 01.
Article in English | MEDLINE | ID: mdl-17583515

ABSTRACT

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.


Subject(s)
Biological Products/chemistry , Diterpenes/chemistry , Hydroquinones/chemical synthesis , Hydroquinones/toxicity , Acetylation , Benzene/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Screening Assays, Antitumor , Humans , Hydroquinones/chemistry , Magnetic Resonance Spectroscopy , Methylation , Molecular Structure , Oxidation-Reduction , Structure-Activity Relationship
8.
Bioorg Med Chem ; 15(4): 1670-8, 2007 Feb 15.
Article in English | MEDLINE | ID: mdl-17197187

ABSTRACT

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.


Subject(s)
Antineoplastic Agents/chemical synthesis , Podophyllotoxin/analogs & derivatives , Podophyllotoxin/pharmacology , Aldehydes , Animals , Antineoplastic Agents/pharmacology , Carboxylic Acids , Cell Line, Tumor , Drug Screening Assays, Antitumor , Humans , Podophyllotoxin/chemical synthesis , Structure-Activity Relationship
9.
Bioorg Med Chem ; 14(21): 7231-40, 2006 Nov 01.
Article in English | MEDLINE | ID: mdl-16842998

ABSTRACT

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.


Subject(s)
Antineoplastic Agents/pharmacology , Quinones/pharmacology , Cell Line , Cell Line, Tumor , Cell Survival/drug effects , Humans , Magnetic Resonance Spectroscopy , Spectrometry, Mass, Fast Atom Bombardment
10.
Bioorg Med Chem ; 14(8): 2816-27, 2006 Apr 15.
Article in English | MEDLINE | ID: mdl-16376545

ABSTRACT

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.


Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Naphthoquinones/chemical synthesis , Naphthoquinones/pharmacology , Cell Line, Tumor , Drug Screening Assays, Antitumor , Humans , Magnetic Resonance Spectroscopy , Spectrometry, Mass, Fast Atom Bombardment
11.
Bioorg Med Chem ; 13(3): 631-44, 2005 Feb 01.
Article in English | MEDLINE | ID: mdl-15739276

ABSTRACT

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.


Subject(s)
Quinones/chemical synthesis , Terpenes/chemistry , Magnetic Resonance Spectroscopy , Quinones/toxicity , Spectrophotometry, Infrared
12.
Eur J Med Chem ; 38(10): 899-911, 2003 Oct.
Article in English | MEDLINE | ID: mdl-14575937

ABSTRACT

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.


Subject(s)
Antiviral Agents/chemical synthesis , Podophyllotoxin/analogs & derivatives , Podophyllotoxin/pharmacology , Animals , Antiviral Agents/pharmacology , Cell Line, Tumor , Cell Survival/drug effects , Chlorocebus aethiops , Herpesvirus 2, Human/drug effects , Humans , Magnetic Resonance Spectroscopy , Molecular Structure , Podophyllotoxin/chemical synthesis , Structure-Activity Relationship , Vero Cells
13.
Arch Pharm (Weinheim) ; 335(9): 427-37, 2002 Nov.
Article in English | MEDLINE | ID: mdl-12447916

ABSTRACT

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.


Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Naphthoquinones/chemical synthesis , Naphthoquinones/pharmacology , Animals , Antineoplastic Agents/chemistry , Cell Division/drug effects , Humans , Inhibitory Concentration 50 , Magnetic Resonance Spectroscopy , Naphthoquinones/chemistry , Rats , Tumor Cells, Cultured
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