RESUMEN
Macrocyclic natural products are plentiful in the bacteria, archaea, and eukaryote domains of life. For the significant advantages that they provide to the producing organisms, evolution has learned how to implement various types of macrocyclization reactions into the different biosynthetic pathways and how to effect them with remarkable ease. Mankind greatly benefits from nature's pool, not least because naturally occurring macrocycles or derivatives thereof serve as important drugs for the treatment of many serious ailments.In stark contrast, macrocyclization reactions are usually perceived as difficult to accomplish by purely chemical means. While it is true that ring closure necessarily entails an entropic loss and may result in the buildup of (considerable) ring strain that must be compensated for in one way or the other, it is also fair to note tremendous methodological advances during the last decades that greatly alleviated this traditional "macrocycle challenge". It is therefore increasingly possible to explore the advantages provided by large as well as medium-size ring systems in a more systematic manner. This venture also holds the promise of increasing the "chemical space" amenable to drug development to a considerable extent.In consideration of this and other important long-term perspectives, it is appropriate to revisit the current state of the art. To this end, a number of vignettes are presented, each of which summarizes a total synthesis project targeting macrocyclic natural products of greatly different chemotypes using a variety of transformations to reach these goals. Although we were occasionally facing "dead ends", which are also delineated for the sake of a complete picture, these case studies illustrate the notion that the formation of a certain macrocyclic perimeter is (usually) no longer seriously limiting. In addition to substantial progress in the "classical" repertoire (macrolactonization and macrolactamization (pateamine A, spirastrellolide, and belizentrin)), various metal-catalyzed reactions have arguably led to the greatest leaps forward. Among them, palladium-catalyzed C-C bond formation (roseophilin and nominal xestocyclamine A) and, in particular, alkene and alkyne metathesis stand out (iejimalide, spirastrellolide, enigmazole, ingenamine, and sinulariadiolide). In some cases, different methods were pursued in parallel, thus allowing for a critical assessment and comparison.To the extent that the macrocyclic challenge is vanishing, the opportunity arises to focus attention on the postmacrocyclization phase. One may stipulate that a well-designed cyclization precursor does not only ensure efficient ring closure but also fosters and streamlines the steps that come after the event. One way to do so is dual (multiple) use in that the functional groups serving the actual cyclization reaction also find productive applications downstream from it rather than being subject to simple defunctionalization. In this context, better insight into the conformational peculiarities of large rings and the growing confidence in their accessibility in a stereochemically well defined format rejuvenate the implementation of transannular reactions or reaction cascades that can lead to rapid and substantial increases in molecular complexity. The examples summarized herein showcase such possibilities, with special emphasis on tranannular gold catalysis and the emerging ruthenium-catalyzed trans-hydrometalation chemistry for the selective functionalization of alkynes.
Asunto(s)
Productos Biológicos/síntesis química , Alquenos/química , Alquinos/química , Productos Biológicos/química , Catálisis , Ciclización , Compuestos Heterocíclicos con 3 Anillos/síntesis química , Compuestos Heterocíclicos con 3 Anillos/química , Lactamas Macrocíclicas/síntesis química , Lactamas Macrocíclicas/química , Macrólidos/síntesis química , Macrólidos/química , Metales/química , Pirroles/síntesis química , Pirroles/química , Compuestos de Espiro/síntesis química , Compuestos de Espiro/químicaRESUMEN
On June 8, 2018, an NS3/4A protease inhibitor called danoprevir was approved in China to treat the infections of HCV genotype (GT) 1b - the most common HCV genotype worldwide. Based on phase 2 and 3 clinical trials, the 12-week regimen of ritonavir-boosted danoprevir (danoprevir/r) plus peginterferon alpha-2a and ribavirin offered 97.1% (200/206) of sustained virologic response at post-treatment week 12 (SVR12) in treatment-naïve non-cirrhotic patients infected with HCV genotype 1b. Adverse events such as anemia, fatigue, fever, and headache were associated with the inclusion of peginterferon alpha-2a and ribavirin in the danoprevir-based regimen. Moreover, drug resistance to danoprevir could be traced to amino acid substitutions (Q80K/R, R155K, D168A/E/H/N/T/V) near the drug-binding pocket of HCV NS3 protease. Despite its approval, the clinical use of danoprevir is currently limited to its combination with peginterferon alpha-2a and ribavirin, thereby driving its development towards interferon-free, ribavirin-free regimens with improved tolerability and adherence. In the foreseeable future, pan-genotypic direct-acting antivirals with better clinical efficacy and less adverse events will be available to treat HCV infections worldwide.
Asunto(s)
Antivirales/farmacología , Ciclopropanos/farmacología , Inhibidores Enzimáticos/farmacología , Hepacivirus/efectos de los fármacos , Hepatitis C/tratamiento farmacológico , Isoindoles/farmacología , Lactamas Macrocíclicas/farmacología , Prolina/análogos & derivados , Sulfonamidas/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Antivirales/síntesis química , Antivirales/química , Ciclopropanos/síntesis química , Ciclopropanos/química , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Genotipo , Hepacivirus/genética , Humanos , Isoindoles/síntesis química , Isoindoles/química , Lactamas Macrocíclicas/síntesis química , Lactamas Macrocíclicas/química , Pruebas de Sensibilidad Microbiana , Prolina/síntesis química , Prolina/química , Prolina/farmacología , Serina Proteasas/metabolismo , Sulfonamidas/síntesis química , Sulfonamidas/química , Proteínas no Estructurales Virales/metabolismoRESUMEN
The nucleophilic attack of amines at C(17) or C(17)/C(20) positions of geldanamycin's (GDM) benzoquinone, via initial 1,4-Michael conjugate addition mechanism, yield new analogs with closed or open ansa-bridges (1-31), respectively. X-ray structures of analogs 22 and 24 reveals an unexpected arrangement of the ansa-bridge in solid (conformer B), that is located between those of conformers A, prevailing in solution (trans-lactam), and C, crucial at binding to Hsp90 (cis-lactam). The structure of a new-type conformer B allows to better understand the molecular recognition mechanism between the GDM analogs and the target Hsp90. Combined analysis of: anticancer test results (SKBR-3, SKOV-3, PC-3, U-87, A-549) and those performed in normal cells (HDF), KD values and docking modes at Hsp90 as well as clogP parameters, reveals that the rigid C(17)-arm (piperidyl, cyclohexyl) with a H-bond acceptor as carbonyl group together with a lipophilicity clogPâ¼3 favor high potency of analogs, even up to IC50 â¼0.08 µM, at improved selectivity (SIHDF > 30), when compared to GDM. The most active 25 show higher anticancer potency than 17-AAG (in SKOV-3 and A-549) as well as reblastatin (in SKBR-3 and SKOV-3). Opening of the ansa-bridge within GDM analogs, at the best case, decreases activity (IC50â¼2 µM) and toxicity in HDF cells (SIHDFâ¼2-3), relative to GDM.
Asunto(s)
Aminas/farmacología , Antineoplásicos/farmacología , Benzoquinonas/farmacología , Lactamas Macrocíclicas/farmacología , Aminas/síntesis química , Aminas/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Benzoquinonas/síntesis química , Benzoquinonas/química , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Teoría Funcional de la Densidad , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Lactamas Macrocíclicas/síntesis química , Lactamas Macrocíclicas/química , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Apurinic/apyrimidinic endonuclease 1 (APE1) is an essential base excision repair enzyme that is upregulated in a number of cancers, contributes to resistance of tumors treated with DNA-alkylating or -oxidizing agents, and has recently been identified as an important therapeutic target. In this work, we identified hot spots for binding of small organic molecules experimentally in high resolution crystal structures of APE1 and computationally through the use of FTMAP analysis ( http://ftmap.bu.edu/ ). Guided by these hot spots, a library of drug-like macrocycles was docked and then screened for inhibition of APE1 endonuclease activity. In an iterative process, hot-spot-guided docking, characterization of inhibition of APE1 endonuclease, and cytotoxicity of cancer cells were used to design next generation macrocycles. To assess target selectivity in cells, selected macrocycles were analyzed for modulation of DNA damage. Taken together, our studies suggest that macrocycles represent a promising class of compounds for inhibition of APE1 in cancer cells.
Asunto(s)
ADN-(Sitio Apurínico o Apirimidínico) Liasa/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Lactamas Macrocíclicas/farmacología , Lactonas/farmacología , Dominio Catalítico , Línea Celular Tumoral , Daño del ADN/efectos de los fármacos , ADN-(Sitio Apurínico o Apirimidínico) Liasa/química , ADN-(Sitio Apurínico o Apirimidínico) Liasa/metabolismo , Descubrimiento de Drogas , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/metabolismo , Humanos , Lactamas Macrocíclicas/síntesis química , Lactamas Macrocíclicas/metabolismo , Lactonas/síntesis química , Lactonas/metabolismo , Simulación del Acoplamiento Molecular , Estructura Molecular , Unión Proteica , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/metabolismo , Bibliotecas de Moléculas Pequeñas/farmacología , Relación Estructura-ActividadRESUMEN
A cancer cell-targeting fluorescent sensor has been developed to image mobile Zn2+ by introducing a biotin group. It shows a highly selective response to Zn2+in vitro, no toxicity in cellulo and images 'mobile' Zn2+ specifically in cancer cells. We believe this probe has the potential to help improve our understanding of the role of Zn2+ in the processes of cancer initiation and development.
Asunto(s)
Biotina/análogos & derivados , Biotina/farmacología , Colorantes Fluorescentes/farmacología , Lactamas Macrocíclicas/farmacología , Zinc/análisis , Biotina/síntesis química , Biotina/toxicidad , Fluorescencia , Colorantes Fluorescentes/síntesis química , Colorantes Fluorescentes/toxicidad , Humanos , Queratinocitos/efectos de los fármacos , Lactamas Macrocíclicas/síntesis química , Lactamas Macrocíclicas/toxicidad , Ligandos , Células MCF-7 , Microscopía Fluorescente , Zinc/metabolismoRESUMEN
Rhodesain (RD) is a parasitic, human cathepsin L (hCatL) like cysteine protease produced by Trypanosoma brucei ( T. b.) species and a potential drug target for the treatment of human African trypanosomiasis (HAT). A library of hCatL inhibitors was screened, and macrocyclic lactams were identified as potent RD inhibitors ( Ki < 10 nM), preventing the cell-growth of Trypanosoma brucei rhodesiense (IC50 < 400 nM). SARs addressing the S2 and S3 pockets of RD were established. Three cocrystal structures with RD revealed a noncovalent binding mode of this ligand class due to oxidation of the catalytic Cys25 to a sulfenic acid (Cys-SOH) during crystallization. The P-glycoprotein efflux ratio was measured and the in vivo brain penetration in rats determined. When tested in vivo in acute HAT model, the compounds permitted up to 16.25 (vs 13.0 for untreated controls) mean days of survival.
Asunto(s)
Catepsina L/antagonistas & inhibidores , Cisteína Endopeptidasas/metabolismo , Inhibidores de Cisteína Proteinasa/farmacología , Lactamas Macrocíclicas/farmacología , Tripanocidas/farmacología , Trypanosoma brucei rhodesiense/efectos de los fármacos , Animales , Sitios de Unión , Barrera Hematoencefálica/metabolismo , Línea Celular , Cisteína Endopeptidasas/química , Inhibidores de Cisteína Proteinasa/síntesis química , Inhibidores de Cisteína Proteinasa/química , Inhibidores de Cisteína Proteinasa/farmacocinética , Reposicionamiento de Medicamentos , Humanos , Lactamas Macrocíclicas/síntesis química , Lactamas Macrocíclicas/química , Lactamas Macrocíclicas/farmacocinética , Ligandos , Masculino , Ratones Endogámicos C57BL , Estructura Molecular , Ratas , Relación Estructura-Actividad , Porcinos , Tripanocidas/síntesis química , Tripanocidas/química , Tripanocidas/farmacocinéticaRESUMEN
It may be useful to develop prodrugs that are selectively activated by oxidative stress in cancer cells to release cell-killing reactive intermediates. However, relatively few chemical strategies exist for the activation of prodrugs under conditions of oxidative stress. Here we provide evidence for a novel process in which oxidation of a thiol residue in the natural product leinamycin E1 by H2O2 and other byproducts of cellular oxidative stress initiates generation of an episulfonium ion that selectively alkylates guanine residues in duplex DNA.
Asunto(s)
Antineoplásicos Alquilantes/química , ADN/química , Guanina/química , Lactamas Macrocíclicas/química , Profármacos/química , Alquilación , Antineoplásicos Alquilantes/síntesis química , Daño del ADN , Compuestos Férricos/química , Peróxido de Hidrógeno/química , Lactamas Macrocíclicas/síntesis química , Oxidación-Reducción , Profármacos/síntesis química , Xantina/química , Xantina Oxidasa/químicaRESUMEN
1,8-Bis(2,2,2-trifluoroethyl)cyclam (te2f) derivatives with two coordinating pendant arms involving methylenecarboxylic acid (H2te2f2a), methylenephosphonic acid (H4te2f2p), (2-pyridyl)methyl (te2f2py), and 2-aminoethyl arms (te2f2ae) in 4,11-positions were prepared, and their nickel(II) complexes were investigated as possible 19F MR tracers. The solid-state structures of several synthetic intermediates, ligands, and all complexes were confirmed by X-ray diffraction analysis. The average Ni···F distances were determined to be about 5.2 Å. All complexes exhibit a trans-III cyclam conformation with pendant arms bound in the apical positions. Kinetic inertness of the complexes is increased in the ligand order te2f2ae ⪠te2f < te2f2py ≈ H4te2f2p ⪠H2te2f2a. The [Ni(te2f2a)] complex is the most kinetically inert Ni(II) complex reported so far. Paramagnetic divalent nickel caused a shortening of 19F NMR relaxation time down to the millisecond range. Solubility, stability, and cell toxicity were only satisfactory for the [Ni(te2f2p)]2- complex. This complex was visualized by 19F MRI utilizing an ultrashort echo time (UTE) imaging pulse sequence, which led to an increase in sensitivity gain. Mesenchymal stem cells were successfully loaded with the complex (up to 0.925/5.55 pg Ni/F per cell).19F MRI using a UTE pulse sequence provided images with a good signal-to-noise ratio within the measurement time, as short as tens of minutes. The data thus proved a major sensitivity gain in 19F MRI achieved by utilization of the paramagnetic (transition) metal complex as 19F MR tracers coupled with the optimal fast imaging protocol.
Asunto(s)
Complejos de Coordinación/farmacología , Lactamas Macrocíclicas/farmacología , Imagen por Resonancia Magnética/métodos , Níquel/química , Radiofármacos/farmacología , Animales , Complejos de Coordinación/síntesis química , Complejos de Coordinación/química , Complejos de Coordinación/toxicidad , Estabilidad de Medicamentos , Radioisótopos de Flúor , Lactamas Macrocíclicas/síntesis química , Lactamas Macrocíclicas/química , Lactamas Macrocíclicas/toxicidad , Ligandos , Células Madre Mesenquimatosas/metabolismo , Estructura Molecular , Radiofármacos/síntesis química , Radiofármacos/química , Radiofármacos/toxicidad , Ratas Endogámicas LewRESUMEN
The Massachusetts General Hospital Radiochemistry Program, in collaboration with Pfizer, has developed unique 11C and 18F-labeling strategies to synthesize isotopologs of lorlatinib (PF-06463922) which is undergoing phase III clinical trial investigations for treatment of non-small-cell lung cancers with specific molecular alterations. A major goal in cancer therapeutics is to measure the concentrations of this drug in the brain metastases of patients with lung cancer, and penetration of the blood-brain barrier is important for optimal therapeutic outcomes. Our recent publication in Nature Communications employed radiolabeled lorlatinib and positron emission tomography (PET) studies in preclinical models including nonhuman primates (NHPs) that demonstrated high brain permeability of this compound. Our future work with radiolabeled lorlatinib will include advanced PET evaluations in rodent tumor models and normal NHPs with the goal of clinical translation.
Asunto(s)
Encéfalo/metabolismo , Lactamas Macrocíclicas/farmacología , Tomografía de Emisión de Positrones , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Aminopiridinas , Quinasa de Linfoma Anaplásico , Animales , Encéfalo/efectos de los fármacos , Humanos , Lactamas , Lactamas Macrocíclicas/síntesis química , Lactamas Macrocíclicas/química , Macaca mulatta , Inhibidores de Proteínas Quinasas/química , Proteínas Tirosina Quinasas/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Pirazoles , Proteínas Tirosina Quinasas Receptoras/metabolismoRESUMEN
Inspired from geldanamycin, the synthesis of a new series of 20-membered macrocyclic compounds is developed. The key features in our design are (i) retention of the fragment having the precise chiral functional groups of geldanamycin at C10, C11, C12 and C14, and (ii) replacement of an olefin moiety with the ester group, and the quinoid sub-structure with the triazole ring. The southern fragment needed for the macrocyclic ring formation was obtained from Evans' syn aldol as the key reaction and with the use of D-mannitol as the cheap source of a chiral starting material. For the synthesis of the northern fragment, we utilized l-ascorbic acid, which provided the desired chiral functional groups at C6 and C7. Further, the chain extension completed the synthesis of the northern fragment. In our approach, the crucial 20 membered macrocyclic ring was formed employing the click chemistry. When tested for their ability to directly trans-differentiate human mesenchymal stem cells to neurons, two novel compounds (20a and 7) from this series were identified and this was further validated by the presence of specific neuronal biomarkers (i.e. nestin, agrin and RTN4).
Asunto(s)
Benzoquinonas/farmacología , Lactamas Macrocíclicas/farmacología , Células Madre Mesenquimatosas/efectos de los fármacos , Neuronas/efectos de los fármacos , Benzoquinonas/síntesis química , Benzoquinonas/química , Diferenciación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Lactamas Macrocíclicas/síntesis química , Lactamas Macrocíclicas/química , Células Madre Mesenquimatosas/citología , Estructura Molecular , Neuronas/citología , Relación Estructura-ActividadRESUMEN
2,3,3',4,4'-Penta-O-benzylsucrose was converted into the corresponding diaminoalcohol which was used as a key building block in the synthesis of the analogues of aza-crown ethers and bis-lactams.
Asunto(s)
Compuestos Corona/síntesis química , Lactamas Macrocíclicas/síntesis química , Sacarosa/química , Catálisis , Estructura MolecularRESUMEN
The chemical modification of macrolide natural products into aza- or lactam analogues is a strategy employed to improve their metabolic stability and biological activity. The methods for the synthesis of several lactam analogues of macrolide natural products are highlighted and aspects of their biological properties presented.
Asunto(s)
Antibacterianos/química , Productos Biológicos/química , Lactamas Macrocíclicas/química , Macrólidos/química , Antibacterianos/síntesis química , Antibacterianos/farmacología , Bacterias/efectos de los fármacos , Productos Biológicos/farmacología , Lactamas Macrocíclicas/síntesis química , Lactamas Macrocíclicas/farmacología , Macrólidos/farmacología , Modelos Moleculares , Conformación MolecularRESUMEN
Heronamides are biosynthetically related metabolites isolated from marine-derived actinomycetes. Heronamideâ C shows potent antifungal activity by targeting membrane phospholipids possessing saturated hydrocarbon chains with as-yet-unrevealed modes of action. In spite of their curious hypothesized biosynthesis and fascinating biological activities, there have been conflicts in regard to the reported stereochemistries of heronamides. Here, we describe the asymmetric total synthesis of the originally proposed and revised structures of heronamideâ C, which unambiguously confirmed the chemical structure of this molecule. We also demonstrated nonenzymatic synthesis of heronamidesâ A and B from heronamideâ C, which not only proved the postulated biosynthesis, but also confirmed the correct structures of heronamidesâ A and B. Investigation of the structure-activity relationship of synthetic and natural heronamides revealed the importance of both long-range stereochemical communication and the 20-membered macrolactam ring for the biological activity of these compounds.
Asunto(s)
Lactamas Macrocíclicas/síntesis química , Actinobacteria/química , Actinobacteria/metabolismo , Antifúngicos/síntesis química , Antifúngicos/química , Antifúngicos/farmacología , Catálisis , Dicroismo Circular , Lactamas Macrocíclicas/química , Lactamas Macrocíclicas/farmacología , Espectroscopía de Resonancia Magnética , Microscopía Fluorescente , Schizosaccharomyces/efectos de los fármacos , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A series of one-pot, sequential protocols was developed for the synthesis of novel macrocycles bearing α,ß-unsaturated chemotypes. The method highlights a phosphate tether-mediated approach to establish asymmetry, and consecutive one-pot, sequential processes to access the macrocycles with minimal purification procedures. This library amenable strategy provided diverse macrocycles containing α,ß-unsaturated carbon-, sulfur-, or phosphorus-based warheads.
Asunto(s)
Compuestos Macrocíclicos/síntesis química , Lactamas Macrocíclicas/síntesis química , Naftalenosulfonatos/síntesis química , EstereoisomerismoRESUMEN
A growing number of natural products appear to arise from biosynthetic pathways that involve pericyclic reactions. We show here that for the heronamides this can occur via two spontaneous pathways involving alternative thermal or photochemical intramolecular cycloadditions.
Asunto(s)
Reacción de Cicloadición , Lactamas Macrocíclicas/química , Lactamas Macrocíclicas/síntesis química , Conformación Molecular , Procesos Fotoquímicos , Streptomyces/químicaRESUMEN
Thiazinogeldanamycin (2) was identified from Streptomyces hygroscopicus 17997 at the late stage of the fermentation. The pH was firstly proposed as an important factor in the biosynthesis of it. It was verified that 2 was produced by direct chemical reactions between geldanamycin (1, GDM) and cysteine or aminoethanethiol hydrochloride at pH > 7 in vitro. The proposed synthesis pathway for compound 2 was also discussed. Eleven new C-19-modified GDM derivatives, including five stable hydroquinone form derivatives, were synthesized, most of which exhibited desirable properties such as lower cytotoxicity, increased water solubility, and potent antitumor activity. Especially, compounds 5 and 8 showed antitumor activities against HepG2 cell with IC50 values of 2.97-6.61 µM, lower cytotoxicity and at least 15-fold higher water solubility compared with 1 in pH 7.0 phosphate buffer.
Asunto(s)
Antineoplásicos , Benzoquinonas , Hidroquinonas/síntesis química , Lactamas Macrocíclicas , Streptomyces/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/aislamiento & purificación , Antineoplásicos/farmacología , Benzoquinonas/síntesis química , Benzoquinonas/química , Benzoquinonas/aislamiento & purificación , Benzoquinonas/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Células Hep G2 , Humanos , Concentración de Iones de Hidrógeno , Hidroquinonas/química , Concentración 50 Inhibidora , Lactamas Macrocíclicas/síntesis química , Lactamas Macrocíclicas/química , Lactamas Macrocíclicas/aislamiento & purificación , Lactamas Macrocíclicas/farmacología , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , SolubilidadRESUMEN
Kendomycin, an ansamycin-type natural product first reported in 1996, possesses a series of attractive bioactivities and a unique all-carbon macrocyclic skeleton. To the date, seven total syntheses, two formal total syntheses and a number of synthetic studies on this hot molecule have been reported. In this short review article, we mainly survey and comment on these efforts regarding the difficult macrocyclization strategies.
Asunto(s)
Antibacterianos/síntesis química , Antineoplásicos/síntesis química , Lactamas Macrocíclicas/síntesis química , Rifabutina/análogos & derivados , Humanos , Rifabutina/síntesis química , Streptomyces/metabolismo , Relación Estructura-ActividadRESUMEN
Azamacrocyclic bifunctional chelating agents (BCAs) are essential for the development of radiopharmaceuticals in nuclear medicine and we wish to prove that their bioconjugation by a function present on a carbon atom of the macrocyclic skeleton is a solution of choice to maintain their in vivo inertness. Based on our very recent methodology using a bisaminal template and selective N-alkylation approach, a new synthesis of conjugable C-functionalised teta, te2a and cb-te2a has been developed. These chelators have indeed a growing interest in nuclear medicine for positron emission tomography (PET) and radioimmunotherapy (RIT) where they show in several cases better complexation properties than dota or dota-like macrocycles, especially with (64)Cu or (67)Cu radioisotopes. Chelators are bearing an isothiocyanate grafting function introduced by C-alkylation to avoid as much as possible a critical decrease of their chelating properties. The synthesis is very efficient and yields the targeted ligands, teta-Ph-NCS, te2a-Ph-NCS and cb-te2a-Ph-NCS without fastidious work-up and could be easily extended to other cyclam based-BCAs. The newly synthetised te2a-Ph-NCS has been conjugated to an anti mCD138 monoclonal antibody (mAb) to evaluate its in vivo behavior and potentiality as BCA and to explore a first attempt of PET-phenotypic imaging in multiple myeloma (MM). Mass spectrometry analysis of the immunoconjugate showed that up to 4 chelates were conjugated per 9E7.4 mAb. The radiolabeling yield and specific activity post-purification of the bioconjugate 9E7.4-CSN-Ph-te2a were 95 ± 2.8% and 188 ± 27 MBq mg(-1) respectively and the immunoreactivity of (64)Cu-9E7.4-CSN-Ph-te2a was 81 ± 7%. Animal experiments were carried out on 5T33-Luc(+) tumor bearing mice, either in subcutaneous or orthotopic. To achieve PET imaging, mice were injected with (64)Cu-9E7.4-CNS-Ph-te2a and acquisitions were conducted 2 and 20 h post-injection (PI). A millimetric bone uptake was localised in a sacroiliac of a MM orthotopic tumor. Nonspecific uptakes were observed at 2 h PI but, unlike for the tumor, a significant decrease was observed at 20 h PI which improves the contrast of the images.
Asunto(s)
Derivados del Benceno/química , Quelantes/química , Radioisótopos de Cobre/química , Isotiocianatos/química , Lactamas Macrocíclicas/química , Mieloma Múltiple/diagnóstico , Tomografía de Emisión de Positrones , Animales , Derivados del Benceno/síntesis química , Quelantes/síntesis química , Femenino , Isotiocianatos/síntesis química , Lactamas Macrocíclicas/síntesis química , Ratones Endogámicos C57BL , Tomografía de Emisión de Positrones/métodos , Radiofármacos/síntesis química , Radiofármacos/químicaRESUMEN
The transannular [6 + 4] cycloaddition proposed as a step in the biosynthesis of heronamide A has been modeled using density functional theory. The proposed cycloaddition is highly stereoselective, affording a single product. The reaction proceeds through an ambimodal transition state that directly leads to a [4 + 2] adduct in addition to the observed [6 + 4] adduct. Interconversion of these adducts is possible via a facile Cope rearrangement. The [6 + 4] adduct is thermodynamically more stable than the [4 + 2] adduct by 5.2 kcal mol(-1) due to a combination of the ring and steric strain in the [4 + 2] product. The results strongly support the plausibility of the proposed transannular [6 + 4] cycloaddition in the biogenesis of heronamide A and may provide insights to designing substrates that selectively undergo [6 + 4] cycloaddition to form unbridged 10-membered rings.
Asunto(s)
Simulación por Computador , Lactamas Macrocíclicas/química , Ciclización , Reacción de Cicloadición , Lactamas Macrocíclicas/síntesis química , Estructura Molecular , TermodinámicaRESUMEN
An efficient method for synthesizing different functionalized azabicyclo[X.Y.0]alkanone amino acid derivatives has been developed employing electrophilic transannular cyclizations of 8-, 9-, and 10-membered unsaturated macrocycles to form 5,5-, 6,5-, 7,5-, and 6,6-fused bicylic amino acids, respectively. Macrocycles were obtained by a sequence featuring peptide coupling of vinyl-, allyl-, homoallyl-, and homohomoallylglycine building blocks followed by ring-closing metathesis. X-ray crystallographic analyses of the 8-, 9-, and 10-membered macrocyclic lactam starting materials as well as certain bicyclic amino acid products provided insight into their conformational preferences as well as the mechanism for the diastereoselective formation of specific azabicycloalkanone amino acids by way of transannular iodolactamization reactions.