RESUMO
AIDS is a pandemic disease caused by HIV that affects 37 million people worldwide. Current antiretroviral therapy slows disease progression but does not eliminate latently infected cells, which resupply active virus, thus necessitating lifelong treatment with associated compliance, cost, and chemoexposure issues. Latency-reversing agents (LRAs) activate these cells, allowing for their potential clearance, thus presenting a strategy to eradicate the infection. Protein kinase C (PKC) modulators-including prostratin, ingenol esters, bryostatin, and their analogs-are potent LRAs in various stages of development for several clinical indications. While LRAs are promising, a major challenge associated with their clinical use is sustaining therapeutically meaningful levels of the active agent while minimizing side effects. Here we describe a strategy to address this problem based on LRA prodrugs, designed for controllable release of the active LRA after a single injection. As intended, these prodrugs exhibit comparable or superior in vitro activity relative to the parent compounds. Selected compounds induced higher in vivo expression of CD69, an activation biomarker, and, by releasing free agent over time, significantly improved tolerability when compared to the parent LRAs. More generally, selected prodrugs of PKC modulators avoid the bolus toxicities of the parent drug and exhibit greater efficacy and expanded tolerability, thereby addressing a longstanding objective for many clinical applications.
Assuntos
Fármacos Anti-HIV/farmacologia , Briostatinas/farmacologia , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , Pró-Fármacos/farmacologia , Proteína Quinase C/metabolismo , Latência Viral/efeitos dos fármacos , Animais , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/uso terapêutico , Briostatinas/síntese química , Briostatinas/uso terapêutico , Linhagem Celular Tumoral , Células Cultivadas , Diterpenos/química , Infecções por HIV/tratamento farmacológico , HIV-1/fisiologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Ésteres de Forbol/química , Pró-Fármacos/síntese química , Pró-Fármacos/uso terapêutico , Proteína Quinase C/efeitos dos fármacosRESUMO
Bryostatins are a class of naturally occurring macrocyclic lactones with a unique fast developing portfolio of clinical applications, including treatment of AIDS, Alzheimer's disease, and cancer. This comprehensive account summarizes the recent progress (2014-present) in the development of bryostatins, including their total synthesis and biomedical applications. An emphasis is placed on the discussion of bryostatin 1, the most-studied analogue to date. This review highlights the synthetic and biological challenges of bryostatins and provides an outlook on their future development.
Assuntos
Antineoplásicos/química , Briostatinas/síntese química , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Briostatinas/farmacologia , Briostatinas/uso terapêutico , Senescência Celular/efeitos dos fármacos , Doenças do Sistema Nervoso Central/tratamento farmacológico , Infecções por HIV/tratamento farmacológico , Humanos , Proteína Quinase C/antagonistas & inibidores , Proteína Quinase C/metabolismoRESUMO
Important strides are being made in understanding the effects of structural features of bryostatinâ 1, a candidate therapeutic agent for cancer and dementia, in conferring its potency toward protein kinaseâ C and the unique spectrum of biological responses that it induces. A critical pharmacophoric element in bryostatinâ 1 is the secondary hydroxy group at the C26 position, with a corresponding primary hydroxy group playing an analogous role in binding of phorbol esters to protein kinase C. Herein, we describe the synthesis of a bryostatin homologue in which the C26 hydroxy group is primary, as it is in the phorbol esters, and show that its biological activity is almost indistinguishable from that of the corresponding compound with a secondary hydroxy group.
Assuntos
Briostatinas/química , Briostatinas/farmacologia , Desenho de Fármacos , Proteína Quinase C/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Animais , Briostatinas/síntese química , Briostatinas/farmacocinética , Linhagem Celular Tumoral , Humanos , Metilação , Camundongos , Proteína Quinase C/metabolismo , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Relação Estrutura-AtividadeRESUMO
Bryostatin 1 is an exceedingly scarce marine-derived natural product that is in clinical development directed at HIV/AIDS eradication, cancer immunotherapy, and the treatment of Alzheimer's disease. Despite this unique portfolio of indications, its availability has been limited and variable, thus impeding research and clinical studies. Here, we report a total synthesis of bryostatin 1 that proceeds in 29 total steps (19 in the longest linear sequence, >80% average yield per step), collectively produces grams of material, and can be scaled to meet clinical needs (~20 grams per year). This practical solution to the bryostatin supply problem also opens broad, facile, and efficient access to derivatives and potentially superior analogs.
Assuntos
Adjuvantes Imunológicos/síntese química , Fármacos Anti-HIV/síntese química , Briostatinas/síntese química , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Latência Viral/efeitos dos fármacos , Adjuvantes Imunológicos/química , Adjuvantes Imunológicos/farmacologia , Adjuvantes Imunológicos/uso terapêutico , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Briostatinas/química , Briostatinas/farmacologia , Briostatinas/uso terapêutico , Erradicação de Doenças , HumanosRESUMO
Protein kinase C (PKC) modulators are currently of great importance in preclinical and clinical studies directed at cancer, immunotherapy, HIV eradication, and Alzheimer's disease. However, the bound conformation of PKC modulators in a membrane environment is not known. Rotational echo double resonance (REDOR) NMR spectroscopy could uniquely address this challenge. However, REDOR NMR requires strategically labeled, high affinity ligands to determine interlabel distances from which the conformation of the bound ligand in the PKC-ligand complex could be identified. Here we report the first computer-guided design and syntheses of three bryostatin analogues strategically labeled for REDOR NMR analysis. Extensive computer analyses of energetically accessible analogue conformations suggested preferred labeling sites for the identification of the PKC-bound conformers. Significantly, three labeled analogues were synthesized, and, as required for REDOR analysis, all proved highly potent with PKC affinities (â¼1 nM) on par with bryostatin. These potent and strategically labeled bryostatin analogues are new structural leads and provide the necessary starting point for projected efforts to determine the PKC-bound conformation of such analogues in a membrane environment, as needed to design new PKC modulators and understand PKC-ligand-membrane structure and dynamics.
Assuntos
Briostatinas/síntese química , Briostatinas/metabolismo , Desenho de Fármacos , Proteína Quinase C/metabolismo , Rotação , Briostatinas/química , Briostatinas/farmacologia , Técnicas de Química Sintética , Ligantes , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Proteína Quinase C/química , Estrutura Terciária de ProteínaRESUMO
Bryostatin 1 is in clinical trials for the treatment of cancer and Alzheimer's disease and is a candidate for a first-in-class approach to HIV/AIDS eradication. It is neither readily available nor optimally suited for clinical use. Using a function oriented synthesis strategy, a new class of bryostatin-inspired analogs was designed with a simplified salicylate-derived subunit, enabling step-economical synthesis (23 total steps) of agents exhibiting bryostatin-like affinity to protein kinase C (PKC).
Assuntos
Briostatinas/síntese química , Briostatinas/farmacologia , Proteína Quinase C/efeitos dos fármacos , Salicilatos/síntese química , Salicilatos/farmacologia , Briostatinas/química , Humanos , Estrutura Molecular , Salicilatos/químicaRESUMO
Bryostatin 1, in clinical trials or preclinical development for cancer, Alzheimer's disease, and a first-of-its-kind strategy for HIV/AIDS eradication, is neither readily available nor optimally suited for clinical use. In preceding work, we disclosed a new class of simplified bryostatin analogs designed for ease of access and tunable activity. Here we describe a final step diversification strategy that provides, in only 25 synthetic steps, simplified and tunable analogs with bryostatin-like PKC modulatory activities.
Assuntos
Briostatinas/síntese química , Briostatinas/farmacologia , Proteína Quinase C/efeitos dos fármacos , Salicilatos/síntese química , Salicilatos/farmacologia , Briostatinas/química , Humanos , Estrutura Molecular , Salicilatos/químicaRESUMO
A convergent synthesis of a des-B-ring bryostatin analogue is described. This analogue was found to undergo an unexpected ring expansion of the bryolactone core to generate the corresponding 21-membered macrocycle. The parent analogue and the ring-expanded product both displayed nanomolar binding affinity for PKC. Despite containing A-ring substitution identical to that of bryostatin 1 and displaying bryostatin-like biological function, the des-B-ring analogues displayed a phorbol-like biological function in cells. These studies shed new light on the role of the bryostatin B-ring in conferring bryo-like biological function to bryostatin analogues.
Assuntos
Antineoplásicos/química , Produtos Biológicos/química , Briostatinas/química , Briozoários/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Produtos Biológicos/síntese química , Produtos Biológicos/farmacologia , Briostatinas/síntese química , Briostatinas/farmacologia , Linhagem Celular Tumoral , Humanos , Modelos Moleculares , Forbóis/farmacologia , Proteína Quinase C/metabolismoRESUMO
The seco-B-ring bryostatin analogue, macrodiolide WN-1, was prepared in 17 steps (longest linear sequence) and 30 total steps with three bonds formed via hydrogen-mediated C-C coupling. This synthetic route features a palladium-catalyzed alkoxycarbonylation of a C2-symmetric diol to form the C9-deoxygenated bryostatin A-ring. WN-1 binds to PKCα (Ki = 16.1 nM) and inhibits the growth of multiple leukemia cell lines. Although structural features of the WN-1 A-ring and C-ring are shared by analogues that display bryostatin-like behavior, WN-1 displays PMA-like behavior in U937 cell attachment and proliferation assays, as well as in K562 and MV-4-11 proliferation assays. Molecular modeling studies suggest the pattern of internal hydrogen bonds evident in bryostatin 1 is preserved in WN-1, and that upon docking WN-1 into the crystal structure of the C1b domain of PKCδ, the binding mode of bryostatin 1 is reproduced. The collective data emphasize the critical contribution of the B-ring to the function of the upper portion of the molecule in conferring a bryostatin-like pattern of biological activity.
Assuntos
Antineoplásicos/química , Briostatinas/química , Briozoários/química , Acetato de Tetradecanoilforbol/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Briostatinas/síntese química , Briostatinas/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Hidrogenação , Leucemia/tratamento farmacológico , Leucemia/metabolismo , Modelos Moleculares , Proteína Quinase C-alfa/metabolismo , Acetato de Tetradecanoilforbol/síntese química , Acetato de Tetradecanoilforbol/farmacologia , Células U937RESUMO
Protein kinase C (PKC) isozymes play central roles in signal transduction on the cell surface and could serve as promising therapeutic targets of intractable diseases like cancer, Alzheimer's disease, and acquired immunodeficiency syndrome (AIDS). Although natural PKC ligands like phorbol esters, ingenol esters, and teleocidins have the potential to become therapeutic leads, most of them are potent tumor promoters in mouse skin. By contrast, bryostatin-1 (bryo-1) isolated from marine bryozoan is a potent PKC activator with little tumor-promoting activity. Numerous investigations have suggested bryo-1 to be a promising therapeutic candidate for the above intractable diseases. However, there is a supply problem of bryo-1 both from natural sources and by organic synthesis. Recent approaches on the synthesis of bryo-1 have focused on its simplification, without decreasing the ability to activate PKC isozymes, to develop new medicinal leads. Another approach is to use the skeleton of natural PKC ligands to develop bryo-1 surrogates. We have recently identified 10-methyl-aplog-1 (26), a simplified analog of tumor-promoting aplysiatoxin (ATX), as a possible therapeutic lead for cancer. This review summarizes recent investigations on the simplification of natural PKC ligands, bryo-1 and ATX, to develop potential medicinal leads.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Briostatinas/síntese química , Briostatinas/farmacologia , Toxinas de Lyngbya/síntese química , Toxinas de Lyngbya/farmacologia , Proteína Quinase C/antagonistas & inibidores , Animais , Antineoplásicos/toxicidade , Briostatinas/toxicidade , Proliferação de Células/efeitos dos fármacos , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Ligantes , Toxinas de Lyngbya/toxicidade , Proteína Quinase C/metabolismo , Relação Estrutura-AtividadeRESUMO
The bryostatins are a group of 20 macrolides isolated by Pettit and co-workers from the marine organism Bugula neritina. Bryostatin 1, the flagship member of the family, has been the subject of intense chemical and biological investigations due to its remarkably diverse biological activities, including promising indications as therapy for cancer, Alzheimer's disease, and HIV. Other bryostatins, however, have attracted far less attention, most probably due to their relatively low natural abundance and associated scarcity of supply. Among all macrolides in this family, bryostatin 7 is biologically the most potent protein kinase C (PKC) ligand (in terms of binding affinity) and also the first bryostatin to be synthesized in the laboratory. Nonetheless, almost no biological studies have been carried out on this agent. We describe herein the total synthesis of bryostatin 7 based on our pyran annulation technology, which allows for the first detailed biological characterizations of bryostatin 7 with side-by-side comparisons to bryostatin 1. The results suggest that the more easily synthesized and less lipophilic bryostatin 7 may be an effective surrogate for bryostatin 1.
Assuntos
Briostatinas/farmacologia , Lipídeos/química , Briostatinas/síntese química , Briostatinas/química , Linhagem Celular Tumoral , Regulação para Baixo , Humanos , Isoenzimas/metabolismo , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Proteína Quinase C/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Frações Subcelulares/enzimologia , Células U937RESUMO
Bryostatin is a unique lead in the development of potentially transformative therapies for cancer, Alzheimer's disease and the eradication of HIV/AIDS. However, the clinical use of bryostatin has been hampered by its limited supply, difficulties in accessing clinically relevant derivatives, and side effects. Here, we address these problems through the step-economical syntheses of seven members of a new family of designed bryostatin analogues using a highly convergent Prins-macrocyclization strategy. We also demonstrate for the first time that such analogues effectively induce latent HIV activation in vitro with potencies similar to or better than bryostatin. Significantly, these analogues are up to 1,000-fold more potent in inducing latent HIV expression than prostratin, the current clinical candidate for latent virus induction. This study provides the first demonstration that designed, synthetically accessible bryostatin analogues could serve as superior candidates for the eradication of HIV/AIDS through induction of latent viral reservoirs in conjunction with current antiretroviral therapy.
Assuntos
Briostatinas/química , Briostatinas/farmacologia , Animais , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Briostatinas/síntese química , Linhagem Celular , Engenharia Química , Desenho de Fármacos , HIV/fisiologia , Humanos , Ésteres de Forbol/química , Ésteres de Forbol/farmacologia , Proteína Quinase C/metabolismo , Ratos , Ativação Viral/efeitos dos fármacosRESUMO
The role of the C(8) gem-dimethyl group in the A-ring of bryostatin 1 has been examined through chemical synthesis and biological evaluation of a new analogue. Assays for biological function using U937, K562, and MV4-11 cells as well as the profiles for downregulation of PKC isozymes revealed that the presence of this group is not a critical determinant for the unique pattern of biological activity of bryostatin.
Assuntos
Antineoplásicos/síntese química , Briostatinas/síntese química , Proteína Quinase C/antagonistas & inibidores , Antineoplásicos/farmacologia , Briostatinas/farmacologia , Adesão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Estrutura Molecular , Proteína Quinase C/metabolismo , Relação Estrutura-Atividade , Acetato de Tetradecanoilforbol/farmacologiaRESUMO
Bryostatin 1 is a naturally occurring complex macrolide with potent anti-neoplastic activity. However, its extremely low natural occurrence has impeded clinical advancement. We developed a strategy directed at the design of simplified and synthetically more accessible bryostatin analogs. Our lead analog, "picolog", can be step-economically produced. Picolog, compared to bryostatin, exhibited superior growth inhibition of MYC-induced lymphoma in vitro. A key mechanism of picolog's (and bryostatin's) activity is activation of PKC. A novel nano-immunoassay (NIA) revealed that picolog treatment increased phospho-MEK2 in the PKC pathway. Moreover, the inhibition of PKC abrogated picolog's activity. Finally, picolog was highly potent at 100 micrograms/kg and well tolerated at doses ranging from 100 micrograms/kg to 1 milligram/kg in vivo for the treatment of our aggressive model of MYC-induced lymphoma. We provide the first in vivo validation that the bryostatin analog, picolog, is a potential therapeutic agent for the treatment of cancer and other diseases.
Assuntos
Briostatinas/farmacologia , Processos de Crescimento Celular/efeitos dos fármacos , Genes myc/fisiologia , Linfoma/genética , Linfoma/patologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Briostatinas/síntese química , Briostatinas/química , Transformação Celular Neoplásica/genética , Células Cultivadas , Regulação para Baixo/efeitos dos fármacos , Feminino , Humanos , Células Jurkat , Camundongos , Modelos Biológicos , Transfecção , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Herein, we report the synthesis of novel ring-expanded bryostatin analogues. By carefully modifying the substrate, a selective and high-yielding Ru-catalyzed tandem enyne coupling/Michael addition was employed to construct the northern fragment. Ring-closing metathesis was utilized to form the 31-membered ring macrocycle of the analogue. These ring-expanded bryostatin analogues possess anticancer activity against several cancer cell lines. Given the difficulty in forming the C16-C17 olefin at a late stage, we also describe our development of a new-generation strategy to access the C7-C27 fragment, containing both the ring B and C subunits.
Assuntos
Antineoplásicos/química , Antineoplásicos/síntese química , Briostatinas/química , Briostatinas/síntese química , Cicloparafinas/química , Macrolídeos/química , Macrolídeos/síntese química , Paládio/química , Rutênio/química , Antineoplásicos/farmacologia , Briostatinas/farmacologia , Catálise , Linhagem Celular Tumoral , Ciclização , Humanos , Macrolídeos/farmacologia , Espectroscopia de Ressonância Magnética , Estrutura Molecular , EstereoisomerismoRESUMO
Marine natural products have become a major source of new chemical entities in the discovery of potential anticancer agents that potently suppress various molecular targets. In particular, the marine macrolides, which include an array of novel biomolecules endowed with outstanding cytotoxic and/or antiproliferative activities, are a prominent class of marine natural products that offer continued promise for breakthroughs in anticancer research. Herein we highlight some recent studies of promising marine macrolides, paying particular attention to their discovery, anticancer activities, mechanisms of action, chemical synthesis, and representative analogues.
Assuntos
Antineoplásicos/química , Macrolídeos/química , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Organismos Aquáticos/química , Briostatinas/síntese química , Briostatinas/química , Briostatinas/farmacologia , Éteres Cíclicos/síntese química , Éteres Cíclicos/química , Éteres Cíclicos/farmacologia , Macrolídeos/síntese química , Macrolídeos/farmacologiaRESUMO
Asymmetric total synthesis of bryostatin 16 was achieved in 26 steps in the longest linear sequence and in 39 total steps from aldehyde 10. A Pd-catalyzed alkyne-alkyne coupling was employed for the first time as a macrocyclization method in a natural product synthesis. A route to convert bryostatin 16 to a new family of bryostatin analogues was developed. Toward this end, 20-epi-bryostatin 7 was synthesized from a bryostatin 16-like intermediate; the key step involves a Re-catalyzed epoxidation/ring-opening reaction. Preliminary biological studies indicated that this new analogue exhibits nanomolar anti-cancer activity against several cancer cell lines.
Assuntos
Antineoplásicos/síntese química , Briostatinas/síntese química , Paládio/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Briostatinas/química , Catálise , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ciclização , Humanos , Concentração Inibidora 50 , Estrutura MolecularRESUMO
In this Focus Review, we give an overview of various bryostatin total syntheses. We also discuss the synthesis of various bryostatin analogues and their biological activity. Work reviewed includes that of Masamune, Evans, Nishiyama and Yamamura, Hale and Manaviazar, Trost, Wender, Keck, Burke, Thomas, and Krische. Our coverage is primarily for the period 2001-2009, since detailed reviews already exist on bryostatin total synthesis work and biology up to this time.
Assuntos
Antineoplásicos/síntese química , Briostatinas/síntese química , Doença de Alzheimer/tratamento farmacológico , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Briostatinas/química , Briostatinas/uso terapêutico , Proteína Quinase C/antagonistas & inibidores , Proteína Quinase C/metabolismoRESUMO
A close structural analogue of bryostatin 1, which differs from bryostatin 1 only by the absence of the C(30) carbomethoxy group (on the C(13) enoate of the B-ring), has been prepared by total synthesis. Biological assays reveal a crucial role for substitution in the bryostatin 1 A-ring in conferring those responses which are characteristic of bryostatin 1 and distinct from those observed with PMA.