Synthesis and Biological Evaluation of New Quinoxaline Derivatives of ICF01012 as Melanoma-Targeting Probes

Abstract

The aim of this study was the synthesis and pharmacokinetic selection of a best melanin-targeting ligand for addressing anticancer agents to pigmented melanoma. Seven quinoxaline carboxamide derivatives were synthesized and radiolabeled with iodine-125. Biodistribution studies of compounds [ (125) I]1a-g performed in melanoma-bearing mice tumor showed significant tumor uptake (range 2.43-5.68%ID/g) within 1 h after i.v. injection. Fast clearance of the radioactivity from the nontarget organs mainly via the urinary system gave high tumor-to-blood and tumor-to-muscle ratios. Given its favorable clearance and high tumor-melanoma uptake at 72 h, amide 1d was the most promising melanoma-targeting ligand in this series. Compound 1d will be used as building block for the design of new melanoma-selective drug delivery systems.

Melanoma-targeted delivery system (part 1): Design, synthesis and evaluation of releasable disulfide drug by glutathione

“…As depicted in Scheme 1A, the asymmetrical disulfide (1) was easily obtained using a literature procedure by oxidation of the thiol function of 2-mercaptopyridine with sulfuryl chloride in the presence of 2-mercaptoethanol [44]. Using a similar method, compound (2a) was obtained in 71% yield from 4-methoxybenzenethiol and 2-mercaptoethanol.…”

Remote loading of liposomes with a 124I-radioiodinated compound and their in vivo evaluation by PET/CT in a murine tumor model

“…[ 124 I]ADA and [ 125 I]ADA were synthesized using an aromatic Finkelstein reaction (iodine-iodine exchange) modified from Aissi et al 42. Amino diatrizoic acid (ADA) (0.35 mg, 0.45 µmol, TFA salt) was dissolved in glacial acetic acid (240 µL) in a glass vial, followed by adding a dispersion of CuSO 4 in glacial acetic acid (120 µL, 1.0 mg/mL, 0.76 µmol).…”

“…Remote loading was accomplished using either citrate- or ammonium sulfate-based pH gradients, and was further optimized by varying the pH of the utilized buffers, the compound-to-lipid ratio, and the duration of the loading procedure. 124 I radioiodinated diatrizoic acid analogues were obtained by an aromatic Finkelstein reaction 42, and were remote loaded into stealth liposomes. The biodistribution of the 124 I-radiolabeled stealth liposomes and the free compound was evaluated by PET/CT imaging and ex vivo gamma counting in tumor-bearing mice.…”

Design, synthesis and evaluation of antiproliferative activity of melanoma-targeted histone deacetylase inhibitors

“… A ) structures of selected melanin-targeting benzamides for imaging melanomas 3b, 3c, 11 ; B ) structures of clinically approved HDACi; C) standard HDACi pharmacophoric model.…”