Synthesis and hydrolytic evaluation of acid-labile imine-linked cytoxic isatin model systems

In this study a series of isatin-based, pH-sensitive aryl imine derivatives with differing aromatic substituents and substitution patterns were synthesised and their acid-catalysed hydrolysis evaluated. These derivatives were functionalised at the C3 carbonyl group of a potent N-substituted isatin cytotoxin and were stable at physiological pH but readily cleaved at pH 4.5. Observed rates of hydrolysis for the embedded imine-acid moiety were in the order para-phenylpropionic acid\u3ephenylacetic acid (para\u3emeta)\u3ebenzoic acid (meta\u3epara). The ability to fine-tune hydrolysis rates in this way has potential implications for optimising imine linked, tumour targeting cytotoxin-protein conjugate

Preclinical evaluation of novel, all-in-one formulations of 5-fluorouracil and folinic acid with reduced toxicity profiles

Objectives: 5-Fluorouracil (5-FU) in combination with its synergistic biomodulator folinic acid maintains a pivotal position in cancer chemotherapy. However, clinical limitations persist with the administration of these drugs in combination including phlebitis and catheter blockages, which are associated with reduced efficacy and/or quality of life for patients. We have previously reported novel all-in-one, pH neutral, parenteral 5-FU and folinic acid formulations (termed Fluorodex) incorporating beta-cyclodextrins. Fluorodex maintains potency while overcoming the accepted incompatibility of 5-FU and folinic acid.Methods: We performed toxicological, pharmacokinetic and biodistribution, and efficacy evaluations of Fluorodex compared to 5-FU:folinic acid using several administration routes and schedules in two rodent models. These were compared to dose-matched sequential administration of 5-FU:folinic acid.Results: Fluorodex showed bioequivalence to 5-FU:folinic acid as assessed by tissue distribution and pharmacokinetics of 5-FU, but was generally better tolerated as determined by weight loss, hematological and other clinical parameters. Compared to 5-FU:folinic acid, Fluorodex was also associated with reduced phlebitis using a rabbit ear vein model. Furthermore, equivalent to enhanced efficacy of Fluorodex compared to 5-FU:folinic acid against human carcinoma tumour models in mice was observed.Conclusions: These novel all-in-one formulations represent a superior injectable form of 5- FU that allows co-delivery of folinic acid. This should translate to improved patient tolerability with potential for enhanced efficacy

N-Phenethyl and N-naphthylmethyl isatins and analogues as in vitro cytotoxic agents

Arange of N-phenethyl,N-phenacyl, and N-(1- and 2-naphthylmethyl) derivatives of 5,7-dibromoisatin 2 were prepared byN-alkylation reactions. Their activity against human monocyte-like histiocytic lymphoma (U937), leukemia (Jurkat), and breast carcinoma (MDA-MB-231) cell lines was assessed. The results allowed further development of structureactivity relationships. The compound 5,7-dibromo-N-(1-naphthylmethyl)-1H-indole-2,3-dione 5a was the most potent against U937 cells with an IC50 value of 0.19 microM