RESUMO
A series of 3-(benzyl-substituted)-imidazo[5,1-d]-1,2,3,5-tetrazines (13) and related derivatives with 3-heteromethyl groups has been synthesised and screened for growth-inhibitory activity in vitro against two pairs of glioma cell lines with temozolomide-sensitive and -resistant phenotypes dependent on the absence/presence of the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT). In general the compounds had low inhibitory activity with GI50 values >50 µM against both sets of cell lines. Two silicon-containing derivatives, the TMS-methylimidazotetrazine (9) and the SEM-analogue (10), showed interesting differences: compound (9) had a profile very similar to that of temozolomide with the MGMT+ cell lines being 5 to 10-fold more resistant than MGMT- isogenic partners; the SEM-substituted compound (10) showed potency across all cell lines irrespective of their MGMT status.
RESUMO
Glioblastoma multiforme (GBM) treatment includes temozolomide (TMZ) chemotherapy. O6-Methylguanine lesions are repaired by methylguanine-DNA methyltransferase (MGMT). Response to TMZ requires low MGMT and functional mismatch repair (MMR); resistance, conferred by MGMT or MMR deficiency, represents a barrier to successful treatment. TMZ analogs were synthesized, substituting N3-methyl with propargyl (1) or sulfoxide (2). MTT assays were conducted in SNB19 and U373 isogenic glioma cell lines (V = vector control; M = MGMT-transfected). TMZ potency was reduced >5-fold in SNB19M and U373M cells; in contrast, MGMT-expressing cells were equisensitive as vector controls to analogs 1 and 2 . GI50 values <50 µM of analogs 1 or 2 were detected in V cells possessing acquired TMZ resistance: SNB19VR (hMSH6 loss) and U373VR (MGMT upregulation). Analogs 1 and 2 inhibited MMR-deficient colorectal carcinoma cell growth (irrespective of p53); G2/M cell cycle arrest preceded apoptosis. γH2AX foci inferred the generation of DNA double-strand breaks by analogs 1 and 2 . Acridine orange-stained vesicles, intracellular punctate GFP-LC3 protein and double-membraned autophagosomes indicate that TMZ, 1 and 2 induce autophagy in apoptotis-resistant GBM cells. Analogs 1 and 2 elicit in vitro antitumor activity irrespective of MGMT, MMR and p53. Such imidazotetrazines may treat MGMT+ GBM and possess broader spectrum activity causing apoptosis and autophagy in malignancies which evade apoptosis.
Assuntos
Antineoplásicos Alquilantes/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Reparo de Erro de Pareamento de DNA/efeitos dos fármacos , Metilases de Modificação do DNA/análise , Enzimas Reparadoras do DNA/análise , Dacarbazina/análogos & derivados , Glioblastoma/tratamento farmacológico , Proteínas Supressoras de Tumor/análise , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quebras de DNA de Cadeia Dupla , Dacarbazina/farmacologia , Glioblastoma/patologia , Histonas/análise , Humanos , Temozolomida , Proteína Supressora de Tumor p53/análise , Proteína Supressora de Tumor p53/fisiologiaRESUMO
The pentacyclic acridinium salt RHPS4 (3,11-difluoro-6,8,13-trimethyl-8H-quino [4,3,2-kl] acridinium methosulfate, compound 1) is one of the most interesting DNA G-quadruplex binding molecules due to its high efficacy in tumor cell growth inhibition both in in vitro models and in vivo against human tumor xenografts in combination with conventional chemotherapeutics. Despite compound 1 having desirable chemical and pharmaceutical properties, its potential as a therapeutic agent is compromised by off-target effects on cardiovascular physiology. In this paper we report a new series of structurally-related compounds which were developed in an attempt to minimize its off-target profile, but maintaining the same favorable chemical and pharmacological features of the lead compound. By performing a comparative analysis it was possible to identify which derivatives had the following properties: (i) to show a reduced capacity in respect to compound 1 to inhibit the hERG tail current tested in a patch clamp assay and/or to interact with the human recombinant ß2 receptor; (ii) to maintain both a good G4-binding affinity and cancer cell selectivity; and (iii) to trigger DNA damage with specific telomere uncapping. These studies allowed us to identify a novel G4-stabilizing molecule, compound 8, being characterized by reduced off-target effects and potent telomere on-target properties compared to the prototypic compound 1. Moreover, compound 8 shares with compound 1 the same molecular mode of action and an anti-tumour activity specifically restricted to replicating cells, as evident with its particularly efficient activity in combination therapy with a topoisomerase I inhibitor. In conclusion, we have identified a new pentacyclic derivative 8 having suitable properties to be the focus of further investigations as a clinical candidate for cancer therapy.
Assuntos
Acridinas/farmacologia , Antineoplásicos/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Dano ao DNA , Desenho de Fármacos , Telômero/efeitos dos fármacos , Acridinas/química , Acridinas/toxicidade , Antineoplásicos/toxicidade , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Relação Dose-Resposta a Droga , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Canais de Potássio Éter-A-Go-Go/metabolismo , Células HT29 , Humanos , Ligantes , Potenciais da Membrana , Estrutura Molecular , Receptores Adrenérgicos beta 2/efeitos dos fármacos , Receptores Adrenérgicos beta 2/metabolismo , Relação Estrutura-Atividade , Telômero/genética , Telômero/metabolismoRESUMO
Quadruplexes DNA are present in telomeric DNA as well as in several cancer-related gene promoters and hence affect gene expression and subsequent biological processes. The conformations of G4 provide selective recognition sites for small molecules and thus these structures have become important drug-design targets for cancer treatment. The DNA G-quadruplex binding pentacyclic acridinium salt RHPS4 (1) has many pharmacological attributes of an ideal telomere-targeting agent but has undesirable off-target liabilities. Notably a cardiovascular effect was evident in a guinea pig model, manifested by a marked and sustained increase in QTcB interval. In accordance with this, significant interaction with the human recombinant ß2 adrenergic receptor, and M1, M2 and M3 muscarinic receptors was observed, together with a high inhibition of the hERG tail current tested in a patch clamp assay. Two related pentacyclic structures, the acetylamines (2) and (3), both show a modest interaction with ß2 adrenergic receptor, and do not significatively inhibit the hERG tail current while demonstrating potent telomere on-target properties comparing closely with 1. Of the two isomers, the 2-acetyl-aminopentacycle (2) more closely mimics the overall biological profile of 1 and this information will be used to guide further synthetic efforts to identify novel variants of this chemotype, to maximize on-target and minimize off-target activities. Consequently, the improvement of toxicological profile of these compounds could therefore lead to the obtainment of suitable molecules for clinical development offering new pharmacological strategies in cancer treatment.
Assuntos
Acridinas/química , Acridinas/farmacologia , Quadruplex G , Telômero/metabolismo , Acridinas/síntese química , Animais , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Cobaias , Humanos , Ligantes , Telomerase/antagonistas & inibidoresRESUMO
Analogues of (dibenzo[b,d]thiophen-4-yl)-2-morpholino-4H-chromen-4-one (NU7441), a potent inhibitor of DNA-dependent protein kinase (DNA-PK; IC50 = 42 ± 2 nM), have been synthesized in which water-solubilizing groups [NHCO(CH2)nNR¹R², where n = 1 or 2 and the moiety R¹R²N was derived from a library of primary and secondary amines, e.g., morpholine] were placed at the 1-position. Several of the newly synthesized compounds exhibited high potency against DNA-PK and potentiated the cytotoxicity of ionizing radiation (IR) in vitro 10-fold or more (e.g., 2-(4-ethylpiperazin-1-yl)-N-(4-(2-morpholino-4-oxo-4H-chromen-8-yl)dibenzo[b,d]thio-phen-1-yl)acetamide, 39; DNA-PK IC50 = 5.0 ± 1 nM, IR dose modification ratio = 13). Furthermore, 39 was shown to potentiate not only IR in vitro but also DNA-inducing cytotoxic anticancer agents, both in vitro and in vivo. Counter-screening against other members of the phosphatidylinositol 3-kinase (PI-3K) related kinase (PIKK) family unexpectedly revealed that some of the compounds were potent mixed DNA-PK and PI-3K inhibitors.
Assuntos
Proteína Quinase Ativada por DNA/antagonistas & inibidores , Morfolinas/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/farmacologia , Células HeLa , Humanos , Morfolinas/químicaRESUMO
The optimization of a potent and highly selective series of dual mTORC1 and mTORC2 inhibitors is described. An initial focus on improving cellular potency whilst maintaining or improving other key parameters, such as aqueous solubility and margins over hERG IC(50), led to the discovery of the clinical candidate AZD8055 (14). Further optimization, particularly aimed at reducing the rate of metabolism in human hepatocyte incubations, resulted in the discovery of the clinical candidate AZD2014 (21).
Assuntos
Morfolinas/farmacologia , Complexos Multiproteicos/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Benzamidas , Processos de Crescimento Celular/efeitos dos fármacos , Células Cultivadas , Hepatócitos/efeitos dos fármacos , Hepatócitos/enzimologia , Hepatócitos/metabolismo , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina , Alvo Mecanístico do Complexo 2 de Rapamicina , PirimidinasRESUMO
Resistance to temozolomide (TMZ), conferred by O6-methylguanine-DNA methyltransferase (MGMT) or mismatch repair (MMR) deficiency, presents obstacles to successful glioblastoma multiforme (GBM) treatment. Activities of novel TMZ analogs, designed to overcome resistance, were tested against isogenic SNB19 and U373 GBM cell lines (V = vector control, low MGMT; M = MGMT overexpression). TMZ and triazene MTIC demonstrated >9-fold resistance in SNB19M cells (cf SNB19V). N-3 methyl ester analog 11 and corresponding triazene 12 inhibited growth of TMZ-sensitive (V) and TMZ-resistant (M) cells (GI(50) <50 µM). Ethyl ester 13 and triazene 14 gave similar profiles. MMR-deficient colorectal carcinoma cells, resistant to TMZ (GI(50) >500 µM), responded to analog 11 and 13 treatment. Cross-resistance to these agents was not observed in cell lines possessing acquired TMZ resistance (SNB19VR; U373VR). Methyl ester 11 blocked SNB19V, SNB19M and SNB19VR cells in S and G(2)/M, causing dose- and time-dependent apoptosis. DNA damage, recruiting excision repair was detected by alkaline comet assay; H2AX phosphorylation indicated a lethal DNA double-strand break formation following analog 11 exposure. Compounds 11 and 13 demonstrated 3.7- and 5.1-fold enhanced activity in base excision repair-deficient Chinese hamster ovary cells; furthermore, poly (ADP-ribose) polymerase-1 inhibition potentiated HCT-116 cells' sensitivity to analog 11. In conclusion, analogs 11 and 13 exert anticancer activity irrespective of MGMT and MMR.
Assuntos
Antineoplásicos Alquilantes/farmacologia , Ciclo Celular/efeitos dos fármacos , Reparo de Erro de Pareamento de DNA/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , DNA de Neoplasias/efeitos dos fármacos , Dacarbazina/análogos & derivados , Glioma/genética , Imidazóis/farmacologia , O(6)-Metilguanina-DNA Metiltransferase/genética , Linhagem Celular Tumoral , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/enzimologia , Neoplasias Colorretais/genética , Dacarbazina/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Glioma/tratamento farmacológico , Glioma/enzimologia , Humanos , Projetos Piloto , Poli(ADP-Ribose) Polimerase-1 , Poli(ADP-Ribose) Polimerases/efeitos dos fármacos , Regiões Promotoras Genéticas/efeitos dos fármacos , TemozolomidaRESUMO
Following the discovery of dibenzo[b,d]thiophen-4-yl)-2-morpholino-4H-chromen-4-one (NU7441) ( Leahy , J. J. J. ; Golding , B. T. ; Griffin , R. J. ; Hardcastle , I. R. ; Richardson , C. ; Rigoreau , L. ; Smith , G. C. M. Bioorg. Med. Chem. Lett. 2004 , 14 , 6083 - 6087) as a potent inhibitor (IC50 = 30 nM) of DNA-dependent protein kinase (DNA-PK), we have investigated analogues in which the chromen-4-one core template has been replaced by aza-heterocyclic systems: 9-substituted 2-morpholin-4-ylpyrido[1,2-a]pyrimidin-4-ones and 8-substituted 2-morpholin-4-yl-1H-quinolin-4-ones. The 8- and 9-substituents were either dibenzothiophen-4-yl or dibenzofuran-4-yl, which were each further substituted at the 1-position with water-solubilizing groups [NHCO(CH2)(n)NR¹R², where n = 1 or 2 and the moiety R¹R²N was derived from a library of primary and secondary amines (e.g., morpholine)]. The inhibitors were synthesized by employing a multiple-parallel approach in which the two heterocyclic components were assembled by Suzuki-Miyaura cross-coupling. Potent DNA-PK inhibitory activity was generally observed across the compound series, with structure-activity studies indicating that optimal potency resided in pyridopyrimidin-4-ones bearing a substituted dibenzothiophen-4-yl group. Several of the newly synthesized compounds (e.g., 2-morpholin-4-yl-N-[4-(2-morpholin-4-yl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)dibenzothiophen-1-yl]acetamide) combined high potency against the target enzyme (DNA-PK IC50 = 8 nM) with promising activity as potentiators of ionizing radiation-induced cytotoxicity in vitro.
Assuntos
Benzopiranos/química , Proteína Quinase Ativada por DNA/antagonistas & inibidores , Piridinas/síntese química , Pirimidinonas/síntese química , Quinolonas/síntese química , Permeabilidade da Membrana Celular , Dano ao DNA/efeitos dos fármacos , Dano ao DNA/efeitos da radiação , Furanos/síntese química , Furanos/química , Furanos/farmacologia , Células HeLa , Humanos , Piridinas/química , Piridinas/farmacologia , Pirimidinonas/química , Pirimidinonas/farmacologia , Quinolonas/química , Quinolonas/farmacologia , Bibliotecas de Moléculas Pequenas , Relação Estrutura-Atividade , Tiofenos/síntese química , Tiofenos/química , Tiofenos/farmacologiaRESUMO
The mammalian target of rapamycin (mTOR) kinase forms two multiprotein complexes, mTORC1 and mTORC2, which regulate cell growth, cell survival, and autophagy. Allosteric inhibitors of mTORC1, such as rapamycin, have been extensively used to study tumor cell growth, proliferation, and autophagy but have shown only limited clinical utility. Here, we describe AZD8055, a novel ATP-competitive inhibitor of mTOR kinase activity, with an IC50 of 0.8 nmol/L. AZD8055 showed excellent selectivity (approximately 1,000-fold) against all class I phosphatidylinositol 3-kinase (PI3K) isoforms and other members of the PI3K-like kinase family. Furthermore, there was no significant activity against a panel of 260 kinases at concentrations up to 10 micromol/L. AZD8055 inhibits the phosphorylation of mTORC1 substrates p70S6K and 4E-BP1 as well as phosphorylation of the mTORC2 substrate AKT and downstream proteins. The rapamycin-resistant T37/46 phosphorylation sites on 4E-BP1 were fully inhibited by AZD8055, resulting in significant inhibition of cap-dependent translation. In vitro, AZD8055 potently inhibits proliferation and induces autophagy in H838 and A549 cells. In vivo, AZD8055 induces a dose-dependent pharmacodynamic effect on phosphorylated S6 and phosphorylated AKT at plasma concentrations leading to tumor growth inhibition. Notably, AZD8055 results in significant growth inhibition and/or regression in xenografts, representing a broad range of human tumor types. AZD8055 is currently in phase I clinical trials.
Assuntos
Antineoplásicos/farmacologia , Morfolinas/farmacologia , Neoplasias Experimentais/tratamento farmacológico , Proteínas Quinases/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Animais , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Camundongos , Camundongos Nus , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases/metabolismo , Serina-Treonina Quinases TOR , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Ataxia telangiectasia (A-T) mutated (ATM) is critical for cell cycle checkpoints and DNA repair. Thus, specific small molecule inhibitors targeting ATM could perhaps be developed into efficient radiosensitizers. Recently, a specific inhibitor of the ATM kinase, KU-55933, was shown to radiosensitize human cancer cells. Herein, we report on an improved analogue of KU-55933 (KU-60019) with K(i) and IC(50) values half of those of KU-55933. KU-60019 is 10-fold more effective than KU-55933 at blocking radiation-induced phosphorylation of key ATM targets in human glioma cells. As expected, KU-60019 is a highly effective radiosensitizer of human glioma cells. A-T fibroblasts were not radiosensitized by KU-60019, strongly suggesting that the ATM kinase is specifically targeted. Furthermore, KU-60019 reduced basal S473 AKT phosphorylation, suggesting that the ATM kinase might regulate a protein phosphatase acting on AKT. In line with this finding, the effect of KU-60019 on AKT phosphorylation was countered by low levels of okadaic acid, a phosphatase inhibitor, and A-T cells were impaired in S473 AKT phosphorylation in response to radiation and insulin and unresponsive to KU-60019. We also show that KU-60019 inhibits glioma cell migration and invasion in vitro, suggesting that glioma growth and motility might be controlled by ATM via AKT. Inhibitors of MEK and AKT did not further radiosensitize cells treated with KU-60019, supporting the idea that KU-60019 interferes with prosurvival signaling separate from its radiosensitizing properties. Altogether, KU-60019 inhibits the DNA damage response, reduces AKT phosphorylation and prosurvival signaling, inhibits migration and invasion, and effectively radiosensitizes human glioma cells.
Assuntos
Movimento Celular , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Glioma/tratamento farmacológico , Glioma/enzimologia , Insulina/metabolismo , Morfolinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Tioxantenos/uso terapêutico , Ataxia Telangiectasia/enzimologia , Ataxia Telangiectasia/patologia , Proteínas Mutadas de Ataxia Telangiectasia , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/metabolismo , Movimento Celular/efeitos dos fármacos , Movimento Celular/efeitos da radiação , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Proteínas de Ligação a DNA/antagonistas & inibidores , Proteínas de Ligação a DNA/metabolismo , Fibroblastos/efeitos dos fármacos , Fibroblastos/enzimologia , Fibroblastos/efeitos da radiação , Raios gama , Glioma/patologia , Humanos , Insulina/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos da radiação , Morfolinas/química , Morfolinas/farmacologia , Invasividade Neoplásica , Fosfosserina/metabolismo , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/metabolismo , Pironas/química , Pironas/farmacologia , Radiossensibilizantes/farmacologia , Radiossensibilizantes/uso terapêutico , Tioxantenos/química , Tioxantenos/farmacologia , Proteínas Supressoras de Tumor/antagonistas & inibidores , Proteínas Supressoras de Tumor/metabolismoRESUMO
We describe a novel series of potent inhibitors of the kinase activity of mTOR. The compounds display good selectivity relative to other PI3K-related kinase family members and, in cellular assays, inhibit both mTORC1 and mTORC2 complexes and exhibit good antiproliferative activity.
Assuntos
Antineoplásicos/química , Diaminas/química , Morfolinas/química , Inibidores de Proteínas Quinases/química , Proteínas Quinases/química , Pirimidinas/química , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Linhagem Celular , Diaminas/síntese química , Diaminas/farmacologia , Descoberta de Drogas , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina , Morfolinas/síntese química , Morfolinas/farmacologia , Complexos Multiproteicos , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases/metabolismo , Proteínas , Pirimidinas/síntese química , Pirimidinas/farmacologia , Relação Estrutura-Atividade , Serina-Treonina Quinases TOR , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/metabolismoRESUMO
Structure-activity relationships have been investigated for inhibition of DNA-dependent protein kinase (DNA-PK) and ATM kinase by a series of pyran-2-ones, pyran-4-ones, thiopyran-4-ones, and pyridin-4-ones. A wide range of IC50 values were observed for pyranones and thiopyranones substituted at the 6-position, with the 3- and 5-positions proving intolerant to substitution. Related pyran-2-ones, pyran-4-ones, and thiopyran-4-ones showed similar IC50 values against DNA-PK, whereas the pyridin-4-one system proved, in general, ineffective at inhibiting DNA-PK. Extended libraries exploring the 6-position of 2-morpholino-pyran-4-ones and 2-morpholino-thiopyrano-4-ones identified the first highly potent and selective ATM inhibitor 2-morpholin-4-yl-6-thianthren-1-yl-pyran-4-one (151C; ATM; IC50=13 nM) and revealed constrained SARs for ATM inhibition compared with DNA-PK. One of the most potent DNA-PK inhibitors identified, 2-(4-methoxyphenyl)-6-(morpholin-4-yl)pyran-4-one (16; DNA-PK; IC50=220 nM) effectively sensitized HeLa cells to the topoisomerase II inhibitor etoposide in vitro.
Assuntos
Antineoplásicos/síntese química , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteína Quinase Ativada por DNA/antagonistas & inibidores , Proteínas de Ligação a DNA/antagonistas & inibidores , Morfolinas/síntese química , Fosfatidilinositol 3-Quinases/química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Piranos/síntese química , Piridonas/síntese química , Pironas/síntese química , Proteínas Supressoras de Tumor/antagonistas & inibidores , Antineoplásicos/química , Antineoplásicos/farmacologia , Proteínas Mutadas de Ataxia Telangiectasia , Proteínas de Ciclo Celular/química , Técnicas de Química Combinatória , Proteínas de Ligação a DNA/química , Etoposídeo/farmacologia , Células HeLa , Humanos , Morfolinas/química , Morfolinas/farmacologia , Proteínas Serina-Treonina Quinases/química , Piranos/química , Piranos/farmacologia , Piridonas/química , Piridonas/farmacologia , Pironas/química , Pironas/farmacologia , Relação Estrutura-Atividade , Inibidores da Topoisomerase II , Proteínas Supressoras de Tumor/químicaRESUMO
A new enantioselective synthesis of Masamune's AB fragment (1) for bryostatin 7 is described. Key steps in the new route include a Meerwein-Ponndorf-Verley reduction to set the O(7) stereocenter and an alkylative union between the dithiane 6 and iodide 5 to construct the C(9)-C(10) bond. Because we have previously published a synthesis of Masamune's C-ring phenyl sulfone 2, our new route to 1 constitutes a formal total synthesis of bryostatin 7; it also corrects the previously reported spectral data for 1 in CDCl3.
Assuntos
Antineoplásicos/síntese química , Macrolídeos/síntese química , Antineoplásicos/química , Briostatinas , Macrolídeos/química , EstereoisomerismoRESUMO
[structure: see text] The synthesis of two truncated bryostatin analogues 2 and 3 is described. High-field NMR measurements on the C-ring analogue 3 in C(2)H(3)CN containing 25% (2)H(2)O have shown that it binds to the CRD2 of human PKC-alpha at virtually the same position as phorbol-13-acetate (PA) and bryostatin 1 (1). NMR titration studies have also revealed that 3 binds to the CRD2 with a potency similar in magnitude to PA but much less potently than 1.
Assuntos
Antineoplásicos/química , Lactonas/química , Proteína Quinase C/química , Antineoplásicos/metabolismo , Sítios de Ligação , Briostatinas , Humanos , Lactonas/metabolismo , Macrolídeos , Ressonância Magnética Nuclear Biomolecular , Ésteres de Forbol , Ligação Proteica , Proteína Quinase C/metabolismo , Proteína Quinase C-alfa , Relação Estrutura-Atividade , TitulometriaRESUMO
This review summarises the main developments that have occurred in bryostatin chemistry over the period 1982 to 2001 and has 117 references.