Skin delivery potency and antitumor activities of temozolomide ester prodrugs

Clinical trials have shown temozolomide to be an effective agent for treatment of malignant melanoma. In order to investigate its suitability for delivery via the skin, a series of temozolomide esters was synthesized as prodrugs. In vitro assays demonstrated temozolomide, temozolomide acid and the hexyl ester equi-effective against selected cancer cell lines. The susceptibility of the esters to enzyme hydrolysis and their effectiveness for application to the skin were investigated. The esters effectively diffuse through rat skin and the hexyl ester demonstrated profound potency for penetrating through skin. Topical application of 5% (w/v) hexyl ester in DMSO solution on a mouse model demonstrated a significant inhibition of tumor growth. These results suggest that temozolomide esters could be an effective alternative to temozolomide in the treatment of skin cancer. © 2005 Elsevier Ireland Ltd. All rights reserved.

Specific pH‐responsive folate‐conjugate microgels designed for antitumor therapy

Colloidal nanosized folate-conjugated hydrogels for targeted chemotherapy were prepared via a versatile and efficient postsynthetic modification pathway starting from P(NPA-co-NIPAM). The modifications included the introduction of 4-methylpyridine as pH-sensitive pendant groups and the conjugation of folic acid to the microgel network. The microgels showed a specific swelling at pH?

Quinols as novel therapeutic agents. 2.1 4-(1-arylsulfonylindol- 2-yl)-4-hydroxycyclohexa-2,5-dien-1-ones and related agents as potent and selective antitumor agents

A series of substituted 4-(1-arylsulfonylindol-2-yl)-4-hydroxycyclohexa-2, 5-dien-1-ones (indolylquinols) has been synthesized on the basis of the discovery of lead compound 1a and screened for antitumor activity. Synthesis of this novel series was accomplished via the "one-pot" addition of lithiated (arylsulfonyl)indoles to 4,4-dimethoxycyclohexa-2,5-dienone followed by deprotection under acidic conditions. Similar methodology gave rise to the related naphtho-, 1H-indole-, and benzimidazole-substituted quinols. A number of compounds in this new series were found to possess in vitro human tumor cell line activity substantially more potent than the recently reported antitumor 4-substituted 4-hydroxycyclohexa-2,5-dien-1-ones1 with similar patterns of selectivity against colon, renal, and breast cell lines. The most potent compound in the series in vitro, 4-(1-benzenesulfonyl-6-fluoro-1H-indol- 2-yl)-4-hydroxycyclohexa-2,5-dienone (1h), exhibits a mean GI50 value of 16 nM and a mean LC50 value of 2.24 μM in the NCI 60-cell-line screen, with LC50 activity in the HCT 116 human colon cancer cell line below 10 nM. The crystal structure of the unsubstituted indolylquinol 1a exhibits two independent molecules, both participating in intermolecular hydrogen bonds from quinol OH to carbonyl O, but one OH group also interacts intramolecularly with a sulfonyl O atom. This interaction, which strengthens upon ab initio optimization, may influence the chemical environment of the bioactive quinol moiety. In vivo, significant antitumor activity was recorded (day 28) in mice bearing subcutaneously implanted MDA-MB-435 xenografts, following intraperitoneal treatment of mice with compound 1a at 50 mg/kg.