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A series of 20 optically pure 3,4-dihydro-5H-pyrido[1',2':1,2]imidazo[4,5-d][1,3]diazepin-5-ones which form a new family of azaheterocycle-fused [1,3]diazepines were synthesized in four steps with 17-66% overall yields. The key step consists of a selective C-acylation reaction of easily accessible 2-aminoimidazo[1,2-a]pyridine at C-3.

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The Duff reaction (HMTA, AcOH or TFA) was studied on substituted [6 + 5] heterocyclic compounds. This reaction provides a useful route to aldehydes for compounds bearing sensitive amide functions. It gives also access to tricyclic lactams of potential biological interest. The formation of an aminomethyl intermediate in the Duff reaction mechanism is unequivocally demonstrated.

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To date, surgery remains the only option for the treatment of chondrosarcoma, which is radio- and chemoresistant due in part to its large extracellular matrix (ECM) and poor vascularity. In case of unresectable locally advanced or metastatic diseases with a poor prognosis, improving the management of chondrosarcoma still remains a challenge. Our team developed an attractive approach of improvement of the therapeutic index of chemotherapy by targeting proteoglycan (PG)-rich tissues using a quaternary ammonium (QA) function conjugated to melphalan (Mel). First of all, we demonstrated the crucial role of the QA carrier for binding to aggrecan by surface plasmon resonance. In the orthotopic model of Swarm rat chondrosarcoma, an in vivo biodistribution study of Mel and its QA derivative (Mel-QA), radiolabeled with tritium, showed rapid radioactivity accumulation in healthy cartilaginous tissues and tumor after [H]-Mel-QA injection. The higher T/M ratio of the QA derivative suggests some advantage of QA-active targeting of chondrosarcoma. The antitumoral effects were characterized by tumor volume assessment, in vivo Tc-NTP 15-5 scintigraphic imaging of PGs,H-HRMAS NMR spectroscopy, and histology. The conjugation of a QA function to Mel did not hamper its in vivo efficiency and strongly improved the tolerability of Mel leading to a significant decrease of side effects (hematologic analyses and body weight monitoring). Thus, QA conjugation leads to a significant improvement of the therapeutic index, which is essential in oncology and enable repeated cycles of chemotherapy in patients with chondrosarcoma. Mol Cancer Ther; 15(11); 2575-85. ©2016 AACR.