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1.
J Med Chem ; 44(26): 4509-23, 2001 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-11741471

RESUMO

The cationic porphyrin 5,10,15,20-tetra-(N-methyl-4-pyridyl)porphyrin (TMPyP4) binds to quadruplex DNA and is thereby an inhibitor of human telomerase (Wheelhouse et al. J. Am. Chem. Soc. 1998, 120, 3261-3262). Herein the synthesis and telomerase-inhibiting activity of a wide range of analogues of TMPyP4 are reported, from which rules for a structure-activity relationship (SAR) have been discerned: (1) stacking interactions are critical for telomerase inhibition, (2) positively charged substituents are important but may be interchanged and combined with hydrogen-bonding groups, and (3) substitution is tolerated only on the meso positions of the porphyrin ring, and the bulk of the substituents should be matched to the width of the grooves in which they putatively lie. This SAR is consistent with a model presented for the complexation of TMPyP4 with human telomeric quadruplex DNA.


Assuntos
Antineoplásicos/síntese química , DNA/química , Inibidores Enzimáticos/síntese química , Porfirinas/síntese química , Telomerase/antagonistas & inibidores , Antineoplásicos/química , Antineoplásicos/farmacologia , Sistema Livre de Células , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Quadruplex G , Células HeLa , Humanos , Modelos Moleculares , Porfirinas/química , Porfirinas/farmacologia , Piridinas/química , Pirróis/química , Relação Estrutura-Atividade
2.
Pharmacol Ther ; 85(3): 141-58, 2000 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-10739869

RESUMO

G-quadruplexes are a family of secondary DNA structures formed in the presence of monovalent cations that consist of four-stranded structures in which Hoogsteen base-pairing stabilizes G-tetrad structures. These structures are proposed to exist in vivo, although direct confirmatory evidence is lacking. Guanine-rich regions of DNA capable of forming G-quadruplex structures are found in a variety of chromosomal regions, including telomeres and promoter regions of DNA. In this review, we describe the design of three separate groups of G-quadruplex-interactive compounds and their interaction with G-quadruplex DNA. Using the first group of compounds (anthraquinones), we describe experiments that provide the proof of concept that a G-quadruplex is required for inhibition of telomerase. Using the second group of compounds (perylenes), we describe the structure of a G-quadruplex-ligand complex and its effect on the dynamics of formation and enzymatic unwinding of the quadruplex. For the third group of compounds (porphyrins), we describe the experiments that relate the biological effects to their interactions with G-quadruplexes.


Assuntos
Desenho de Fármacos , Guanina/metabolismo , Conformação de Ácido Nucleico , Telomerase/antagonistas & inibidores , Sequência de Bases , Sítios de Ligação , Divisão Celular , Inibidores Enzimáticos/metabolismo , Guanina/química , Humanos , Ligantes , Dados de Sequência Molecular , Perileno/metabolismo , Regiões Promotoras Genéticas , Telomerase/metabolismo
3.
Cancer Res ; 59(3): 639-44, 1999 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-9973212

RESUMO

A series of cationic porphyrins has been identified as G-quadruplex interactive agents (QIAs) that stabilize telomeric G-quadruplex DNA and thereby inhibit human telomerase; 50% inhibition of telomerase activity was achieved in HeLa cell-free extract at porphyrin concentrations in the range < or = 50 microM. Cytotoxicity of the porphyrins in vitro was assessed in normal human cells (fibroblast and breast) and human tumor cells representing models selected for high telomerase activity and short telomeres (breast carcinoma, prostate, and lymphoma). In general, the cytotoxicity (EC50, effective concentration for 50% inhibition of cell proliferation) against normal and tumor cells was > 50 microM. The porphyrins were readily absorbed into tumor cell nuclei in culture. Inhibition of telomerase activity in MCF7 cells by subcytotoxic concentrations of TMPyP4 showed time and concentration dependence at 1-100 microM TMPyP4 over 15 days in culture (10 population doubling times). The inhibition of telomerase activity was paralleled by a cell growth arrest in G2-M. These results suggest that relevant biological effects of porphyrins can be achieved at concentrations that do not have general cytotoxic effects on cells. Moreover, the data support the concept that a rational, structure-based approach is possible to design novel telomere-interactive agents with application to a selective and specific anticancer therapy.


Assuntos
Antineoplásicos/farmacologia , DNA/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Porfirinas/farmacologia , Antineoplásicos/toxicidade , Neoplasias da Mama/tratamento farmacológico , Cátions , Núcleo Celular/metabolismo , DNA/metabolismo , DNA de Neoplasias/efeitos dos fármacos , DNA de Neoplasias/metabolismo , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/toxicidade , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Quadruplex G , Células HeLa , Humanos , Modelos Moleculares , Neoplasias/metabolismo , Porfirinas/farmacocinética , Porfirinas/toxicidade , Telomerase/antagonistas & inibidores , Telomerase/metabolismo , Células Tumorais Cultivadas
4.
Anticancer Drug Des ; 14(4): 355-65, 1999 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-10625928

RESUMO

Cationic porphyrins, which interact with guanine quadruplex (G4) telomeric folds, inhibit telomerase activity in human tumor cells. In this study, we have further examined effects of porphyrins and other telomere- and telomerase-interactive agents on proliferation rates and chromosome stability in a novel in vivo model, developing sea urchin embryos. We studied two porphyrins: (i) TMPyP4, a potent telomerase inhibitor; and (ii) TMPyP2, an isomer of TMPyP4 and an inefficient telomerase inhibitor, azidothymine (AZT), the reverse transcriptase inhibitor, antisense phosphorothioate oligonucleotide to telomerase RNA (TAG6) and a control scrambled sequence (ODN). TMPyP4, AZT and TAG6 (but not TMPyP2 or ODN) decreased the rates of cell proliferation and increased the percentage of cells trapped in mitosis. Nuclear localization of TAG6, but not of ODN, was demonstrated with 5'-fluoresceinated analogs of TAG6 and ODN. Formation of elongated chromosomes incapable of separating in anaphase, induced by TMPyP4, AZT and TAG6, closely resembled phenotypes resulting from telomerase template mutation or dominant negative TRF2 allele. Our data suggest that G4-interactive agents exert their antiproliferative effects via chromosomal destabilization and warrant their further development as valuable anticancer tools.


Assuntos
Cromossomos/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Porfirinas/farmacologia , Ouriços-do-Mar/embriologia , Telomerase/antagonistas & inibidores , Telômero/efeitos dos fármacos , Animais , Divisão Celular/efeitos dos fármacos , Oligonucleotídeos Antissenso/farmacologia , Telomerase/metabolismo , Zidovudina/farmacologia
6.
Anticancer Drug Des ; 10(3): 215-26, 1995 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-7748456

RESUMO

The 2-amino-6-phenylpyrimidin-4(3H)-ones bropirimine (1) and the debrominated analogue (4) undergo electrophilic nitration and sulphonation in the meta-position of the 6-phenyl group in strongly acidic conditions. Subsequent electrophilic substitutions take place in the 5-position of the pyrimidine ring, if vacant. Rearrangement of the 2-nitramino-6-phenyl-pyrimidines (22) and (23) furnishes the 2-amino-6-(3-nitrophenyl)pyrimidines (9) and (18), respectively. Nucleophilic substitutions, in contrast, occur readily in the pyrimidine 2-, 4- and 6-positions. Debromination of bropirimine by hydrazine hydrate can be rationalized by invoking an initial attack by the nucleophile at the electron-deficient pyrimidine 6-position. The reactive 4-chloro group in 5-bromo-4-chloro-2-formylamino-6-phenylpyrimidine (25) can be displaced with a range of nucleophiles (azide ion, ethanol, hydrazine, and primary and secondary aliphatic amines), without loss of the bromo substituent.


Assuntos
Adjuvantes Imunológicos/química , Citosina/análogos & derivados , Citosina/química , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Estrutura Molecular , Espectrofotometria Infravermelho
7.
J Med Chem ; 38(9): 1493-504, 1995 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-7739008

RESUMO

A series of new imidazo[5,1-d]-1,2,3,5-tetrazinones with additional hydrogen-bonding or ionic substituents at the 8-carboxamide position of the antitumor drugs temozolomide (1) and mitozolomide (2) has been prepared. None of these compounds were significantly more cytotoxic in vitro against the mouse TLX5 lymphoma than the lead structures. Molecular modeling techniques have been used to design benzo- and pyrazolo[4,3-d]-1,2,3-triazinones bearing carboxamide groups in appropriate positions which are isosteric with temozolomide and mitozolamide but which cannot ring open to alkylating species. As predicted, these compounds have no inhibitory properties against human GM892A or Raji cell lines in vitro. Temozolomide and the spermidine-temozolomide conjugate 28 preferentially methylate guanines within guanine-rich sequences in DNA, but no experimental evidence has been found to support the hypothesis that such regions are involved in catalyzing the ring opening of the imidazotetrazinone prodrugs to their active forms.


Assuntos
Antineoplásicos/síntese química , Dacarbazina/análogos & derivados , Compostos Heterocíclicos/síntese química , Animais , Antineoplásicos/farmacologia , Sequência de Bases , Sobrevivência Celular/efeitos dos fármacos , DNA/efeitos dos fármacos , DNA/metabolismo , Primers do DNA , Dacarbazina/química , Dacarbazina/farmacologia , Compostos Heterocíclicos/farmacologia , Camundongos , Modelos Moleculares , Sondas Moleculares , Dados de Sequência Molecular , Temozolomida , Células Tumorais Cultivadas
8.
Biochemistry ; 33(31): 9045-51, 1994 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-8049205

RESUMO

The hypothesis that the antitumor prodrug temozolomide is ring-opened to MTIC which then further breaks down to a reactive diazonium ion at guanine-rich sequences in DNA has been probed by NMR spectroscopy and computational techniques. Temozolomide is stable at acid pH but decomposes to MTIC at pH > 7; in contrast, MTIC is stable at alkaline pH values but rapidly fragments in a methylating mode at pH < 7. The proximate methylating agent is the reactive methyldiazonium species. Runs of guanine residues represent an accessible nucleophilic microenvironment in DNA site-specific conversion of the prodrug temozolomide to MTIC possibly via an activated water molecule in the major groove. Molecular modeling of the structure of temozolomide indicates that the prodrug can make a favorable noncovalent encounter with DNA. The known structure-activity relationships as well as the biological and clinical properties of temozolomide can be interpreted in terms of this model.


Assuntos
Antineoplásicos/química , DNA/química , Dacarbazina/análogos & derivados , Conformação de Ácido Nucleico , Calorimetria , Dacarbazina/química , Estabilidade de Medicamentos , Concentração de Íons de Hidrogênio , Espectroscopia de Ressonância Magnética/métodos , Conformação Molecular , Estrutura Molecular , Temozolomida
9.
Cancer Res ; 52(15): 4190-5, 1992 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-1638533

RESUMO

Many tumor cells, including murine ADJ/PC6 plasmacytoma cells, possess an active energy dependent polyamine uptake system which selectively accumulates endogenous polyamines and structurally related compounds. We have attempted to target the cytotoxic drug chlorambucil to a tumor possessing this uptake system by conjugating it to the polyamine spermidine. Furthermore, since polyamines have a high affinity for DNA, the attachment of spermidine to chlorambucil should also facilitate its targeting to DNA. This was supported by the observation that the chlorambucil-spermidine conjugate was approximately 10,000-fold more active than chlorambucil at forming interstrand crosslinks with naked DNA. In vitro cytotoxicity and in vivo antitumor studies were carried out using the ADJ/PC6 plasmacytoma. In vitro, using [3H]thymidine incorporation to assess cell viability following a 1-h exposure to control and polyamine depleted ADJ/PC6 cells, chlorambucil-spermidine was 35- and 225-fold, respectively, more toxic than chlorambucil. The increased toxicity of the conjugate compared to chlorambucil was possibly due to enhanced DNA binding and/or facilitated uptake via the polyamine uptake system. The enhanced toxicity of the conjugate but not chlorambucil by prior polyamine depletion with difluoromethylornithine, together with the observation that the conjugate but not chlorambucil competitively inhibited spermidine uptake into tumor cells, supported the suggestion that the conjugate utilized the polyamine uptake system. In vivo following a single i.p. dose, the conjugate was 4-fold more potent than chlorambucil in its ability to inhibit ADJ/PC6 tumor growth in BALB/c mice. However, the therapeutic index was not increased. Our results support the hypothesis that polyamines linked to cytotoxics facilitate their entry into tumor cells possessing a polyamine uptake system and increase their selectivity to DNA. This may have therapeutic application in the delivery of cytotoxic agents linked to polyamines to certain tumors.


Assuntos
Sobrevivência Celular/efeitos dos fármacos , Clorambucila/análogos & derivados , Reagentes de Ligações Cruzadas/farmacologia , Replicação do DNA/efeitos dos fármacos , DNA de Neoplasias/efeitos dos fármacos , Espermidina/análogos & derivados , Animais , Clorambucila/farmacologia , DNA de Neoplasias/metabolismo , Portadores de Fármacos , Camundongos , Plasmocitoma , Plasmídeos/efeitos dos fármacos , Espermidina/metabolismo , Espermidina/farmacologia , Timidina/metabolismo , Células Tumorais Cultivadas
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