RESUMEN
A strategy for creating potent and pan-genotypic stimulator of interferon genes (STING) agonists is described. Locking a bioactive U-shaped conformation of cyclic dinucleotides by introducing a transannular macrocyclic bridge between the nucleic acid bases leads to a topologically novel macrocycle-bridged STING agonist (MBSA). In addition to substantially enhanced potency, the newly designed MBSAs, exemplified by clinical candidate E7766, exhibit broad pan-genotypic activity in all major human STING variants. E7766 is shown to have potent antitumor activity with long lasting immune memory response in a mouse liver metastatic tumor model. Two complementary stereoselective synthetic routes to E7766 are also described.
Asunto(s)
Antineoplásicos/farmacología , Interferones/agonistas , Compuestos Macrocíclicos/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Compuestos Macrocíclicos/síntesis química , Compuestos Macrocíclicos/química , Ratones , Modelos Moleculares , Estructura Molecular , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/patologíaRESUMEN
BACKGROUND: Chlorotoxin (Cltx) isolated from scorpion venom is an established tumor targeting and antiangiogenic peptide. Radiolabeled Cltx therapeutic (131I-TM601) yielded promising results in human glioma clinical studies, and the imaging agent tozuleristide, is under investigation in CNS cancer studies. Several binding targets have previously been proposed for Cltx but none effectively explain its pleiotropic effects; its true target remains ambiguous and is the focus of this study. METHODS: A peptide-drug conjugate (ER-472) composed of Cltx linked to cryptophycin as warhead was developed as a tool to probe the molecular target and mechanism of action of Cltx, using multiple xenograft models. RESULTS: Neuropilin-1 (NRP1), an endocytic receptor on tumor and endothelial cells, was identified as a novel Cltx target, and NRP1 binding by Cltx increased drug uptake into tumor. Metabolism of Cltx to peptide bearing free C-terminal arginine, a prerequisite for NRP1 binding, took place in the tumor microenvironment, while native scorpion Cltx with amidated C-terminal arginine did not bind NRP1, and instead acts as a cryptic peptide. Antitumor activity of ER-472 in xenografts correlated to tumor NRP1 expression. Potency was significantly reduced by treatment with NRP1 blocking antibodies or knockout in tumor cells, confirming a role for NRP1-binding in ER-472 activity. Higher cryptophycin metabolite levels were measured in NRP1-expressing tumors, evidence of NRP1-mediated enhanced drug uptake and presumably responsible for the superior antitumor efficacy. CONCLUSIONS: NRP1 was identified as a novel Cltx target which enhances tumor drug uptake. This finding should facilitate tumor selection for chlorotoxin-based therapeutics and diagnostics.
Asunto(s)
Antineoplásicos/metabolismo , Antineoplásicos/farmacología , Neuropilina-1/metabolismo , Venenos de Escorpión/metabolismo , Venenos de Escorpión/farmacología , Secuencia de Aminoácidos , Animales , Antineoplásicos/química , Transporte Biológico , Línea Celular Tumoral , Depsipéptidos/química , Humanos , Ratones , Neuropilina-1/química , Venenos de Escorpión/químicaRESUMEN
Microtubule-targeting agents (MTA) have been investigated for many years as payloads for antibody-drug conjugates (ADC). In many cases, these ADCs have shown limited benefits due to lack of efficacy or significant toxicity, which has spurred continued investigation into novel MTA payloads for next-generation ADCs. In this study, we have developed ADCs using the MTA eribulin, a derivative of the macrocyclic polyether natural product halichondrin B, as a payload. Eribulin ADCs demonstrated in vitro potency and specificity using various linkers and two different conjugation approaches. MORAb-202 is an investigational agent that consists of the humanized anti-human folate receptor alpha (FRA) antibody farletuzumab conjugated via reduced interchain disulfide bonds to maleimido-PEG2-valine-citrulline-p-aminobenzylcarbamyl-eribulin at a drug-to-antibody ratio of 4.0. MORAb-202 displayed preferable biophysical properties and broad potency across a number of FRA-positive tumor cell lines as well as demonstrated improved specificity in vitro compared with farletuzumab conjugated with a number of other MTA payloads, including MMAE, MMAF, and the reducible maytansine linker-payload sulfo-SPDB-DM4. A single-dose administration of MORAb-202 in FRA-positive human tumor cell line xenograft and patient-derived tumor xenograft models elicited a robust and durable antitumor response. These data support further investigation of MORAb-202 as a potential new treatment modality for FRA-positive cancers, using the novel MTA eribulin as a payload.
Asunto(s)
Anticuerpos Monoclonales Humanizados/farmacología , Antineoplásicos/farmacología , Receptor 1 de Folato/antagonistas & inhibidores , Furanos/farmacología , Inmunoconjugados/farmacología , Cetonas/farmacología , Microtúbulos/metabolismo , Animales , Anticuerpos Monoclonales Humanizados/química , Antineoplásicos/química , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Femenino , Receptor 1 de Folato/metabolismo , Furanos/química , Humanos , Inmunoconjugados/química , Cetonas/química , Ratones SCID , Polietilenglicoles/química , Resultado del TratamientoRESUMEN
New synthetic methods for the construction of novel heterocycles and tryptamines are described. Thus, N-Boc anilines (I) are sequentially converted to heterocycles II ((3-(2-aminophenyl)pyrrolidin-3-ol) derivatives), III (substituted 2-oxo-1,2-dihydrospirobenzo[d][1,3]oxazine-4,3'-pyrrolidines), and VI (2-(4,5-dihydro-1H-pyrrol-3-yl)aniline) derivatives through a route involving t-BuLi induced ortho-metalation/LaCl(3).2LiCl metal exchange, reaction with N-Boc pyrrolidin-3-one (5), and subsequent decarboxylative fragmentation. Labile intermediates VI are effectively converted to tryptamines Xa and Xb under controlled protic acid conditions. In addition to providing expedient access to the 2-oxo-1,2-dihydrospirobenzo[d][1,3]oxazine-4,3'-pyrrolidines (III), the method is applicable to the synthesis of the corresponding 2-oxo-1,2-dihydrospirobenzo[d][1,3]oxazine-4,3'-piperidine series of spirocycles (e.g., 42) and their precursors (3-(2-aminophenyl)piperidin-3-ol derivatives, e.g., 43) by using N-Boc-protected piperidin-3-one (40). Applications of the developed synthetic technologies to the synthesis of regioisomeric spirocycles 87 and 90, tryptamines 88 and 91, Corey's aspidophytine tryptamine (97), and efavirenz (1) are also described.
Asunto(s)
Compuestos Heterocíclicos/síntesis química , Triptaminas/síntesis química , Compuestos Heterocíclicos/química , Espectroscopía de Resonancia Magnética , Triptaminas/químicaRESUMEN
An expedient asymmetric total synthesis of aspidophytine is reported. A highly convergent strategy involving the sequential annulation of vinyl iodide 5 with indole 6 exploits varying modes of indole reactivity to provide aspidophytine in 23% over six steps from 5.
Asunto(s)
Compuestos Heterocíclicos de 4 o más Anillos/síntesis química , Alcaloides Indólicos/síntesis química , Cristalografía por Rayos X , Compuestos Heterocíclicos de 4 o más Anillos/química , Alcaloides Indólicos/química , Indoles/química , Lactonas/química , Oxidación-Reducción , Compuestos de Vinilo/químicaRESUMEN
Gambierol, a representative of the marine ladder toxin family, consists of eight ether rings, 18 stereocenters, and two challenging pyranyl rings having methyl groups that are in a 1,3-diaxial orientation to one another. Herein we describe the generation of gambierol's A-C and F-H ring systems and demonstrate the versatility of the glycosyl anhydride, enol ether-olefin RCM strategy to fused polycyclic ethers. This work has both enabled us to generate sufficient quantities of the gambierol precursors and has enabled us to better understand the chemical transformations that were key to these efforts. Fundamental work included efforts to C-glycosides and C-ketosides, Claisen rearrangements, and enol ether-olefin RCM reactions.
Asunto(s)
Ciguatoxinas/síntesis química , Éteres Cíclicos/síntesis química , Glicósidos/síntesis química , Toxinas Marinas/síntesis química , Compuestos Policíclicos/síntesis química , Intoxicación por Ciguatera , Ciclización , Compuestos Epoxi/síntesis química , Éteres/química , Indicadores y Reactivos , Espectroscopía de Resonancia Magnética , Compuestos Policíclicos/químicaRESUMEN
The preceding manuscript detailed our synthesis of the gambierol A-C and F-H ring precursors. Reported herein is a description of the coupling of the two precursors and the conversion of the coupled material into gambierol. Coupling of the subunits involved ester formation, enol ether RCM, and mixed thioketal formation and reduction. By employing this strategy we were able to bring highly advanced subunits into the coupling and, as a result, we were able to minimize the number of post-coupling transformations required to complete gambierol. At the completion of the synthesis, we generated 7.5 mg (1.5 % overall yield) of (-)-gambierol in 44 steps (longest linear sequence).
Asunto(s)
Ciguatoxinas/síntesis química , Éteres Cíclicos/síntesis química , Compuestos Policíclicos/síntesis química , Catálisis , Ciclización , Ésteres/síntesis química , Indicadores y ReactivosRESUMEN
This communication describes the total synthesis of the marine polyether toxin, gambierol. This work couples our iterative C-glycoside/enol ether-olefin metathesis strategy to the subunits with a unique olefin metathesis/carbonyl olefination reaction to bring the subunits together.
Asunto(s)
Ciguatoxinas/síntesis química , Éteres Cíclicos/síntesis química , Compuestos Policíclicos/síntesis química , Animales , Dinoflagelados/química , Glicósidos/químicaRESUMEN
[structure: see text] This manuscript describes our synthesis of the F-H subunit of gambierol. In addition to the synthesis of the tricycle, of note is an interesting protecting group influence on the generation of a C(23) C-glycoside as well as the use of ring-closing metathesis to generate a tetrasubstituted enol ether.
Asunto(s)
Ciguatoxinas , Dinoflagelados/química , Éteres Cíclicos/síntesis química , Glicósidos/química , Compuestos Policíclicos/síntesis química , Animales , Ciclización , Indicadores y Reactivos , Oxidación-ReducciónRESUMEN
The synthesis and characterization of the first stable trialkyl(difluoroamino)silane, R3SiNF2, as well as of R3SiNHF and R3SiN(CH3)F in moderate yields are reported. The (difluoroamino)silane has promise as a new synthon for the introduction of the -NF2 group into a variety of electrophilic inorganic and organic substrates. Activation barriers and relative energies were calculated for the unimolecular decompositions of Me3SiCF3 and t-Bu3SiNF2 using density functional theory (B3LYP/6-31G). The calculated activation energies confirm the long-assumed kinetic stability of Me3SiCF3.