RESUMEN
Antibody-Drug Conjugates (ADCs) are growing in importance for the treatment of both solid and haematological malignancies. There is a demand for new payloads with novel mechanisms of action that may offer enhanced therapeutic efficacy, especially in patients who develop resistance. We report here a class of Cyclopropabenzindole-Pyridinobenzodiazepine (CBI-PDD) DNA cross-linking payloads that simultaneously alkylate guanine (G) and adenine (A) bases in the DNA minor groove with a defined sequence selectivity. The lead payload, FGX8-46 (6), produces sequence-selective G-A cross-links and affords cytotoxicity in the low picomolar region across a panel of 11 human tumour cell lines. When conjugated to the antibody cetuximab at an average Drug-Antibody Ratio (DAR) of 2, an ADC is produced with significant antitumour activity at 1 mg/kg in a target-relevant human tumour xenograft mouse model with an unexpectedly high tolerability (i.e., no weight loss observed at doses as high as 45 mg/kg i.v., single dose).
Asunto(s)
Neoplasias Hematológicas , Inmunoconjugados , Animales , Anticuerpos , Secuencia de Bases , Línea Celular Tumoral , ADN/metabolismo , Humanos , Inmunoconjugados/farmacología , Inmunoconjugados/uso terapéutico , RatonesRESUMEN
The first total synthesis of myrmicine ant alkaloid 5-epi-cis-275B' (4) is presented. A tandem cyclisation established the entire core of the structure in a single transformation as well as the required 2,5-anti stereochemistry. Two-directional synthesis was used to furnish the cyclisation precursor 2, as in each of the subsequent steps towards the natural product. The first electrophysiology studies for 4 (against nicotinic acetylcholine receptors) were also conducted, finding modest inhibition of current.
Asunto(s)
Alcaloides/síntesis química , Alcaloides/farmacología , Quinolinas/síntesis química , Quinolinas/farmacología , Receptores Nicotínicos/fisiología , Acetilcolina/farmacología , Productos Biológicos , Línea Celular , Agonistas Colinérgicos/farmacología , Ciclización , HumanosRESUMEN
The cycloaddition of chiral tert-butanesulfinimines with trimethylenemethane is found to give facile access to methylene-pyrrolidines with good yields and diastereoselectivities. The full scope of the cycloaddition is explored, and a range of transformations of the formed methylenepyrrolidines to give a range of functionalized chiral pyrrolidines is presented.
