Abstract
DDO-6101, a simplified structure obtained from the Garcinia natural product (NP) gambogic acid (GA), has been previously shown to possess high cytotoxicity to a variety of human tumour cell lines. To improve its physicochemical properties and in vivo cytotoxic potency, a series of novel carbamate-bearing derivatives based on DDO-6101 was synthesized and characterized. The structural modifications revealed that the presence of a carbamate moiety was useful for obtaining comparable cytotoxicity and improved aqueous solubility and permeability. 8n, which contains a bipiperidine carbamate moiety, displayed better drug properties and potential in in vivo antitumor activity. In addition, an antitumor mechanistic study suggested that 8n (DDO-6337) inhibited the ATPase activity of Hsp90 (Heat shock protein 90), leading to the inhibition of HIF-1a and ultimately contributing to its anti-angiogenesis and antitumor properties.