Development of novel water-soluble photocleavable protective group and its application for design of photoresponsive paclitaxel prodrugs.
A novel coumarin-based highly water-soluble photocleavable protective group was designed and synthesized, and then this photosensitive protecting group was used to design paclitaxel prodrugs. These novel paclitaxel conjugates demonstrated excellent water solubility, over 100mgmL(-1). Thus, the use of a detergent in the formulation can be omitted completely, even at high doses. Phototaxel 11 released the parent drug, paclitaxel, quickly and efficiently by minimal tissue-damaging 365nm UV light irradiation at low power, while laser activation at 355nm led to extensive decomposition of the prodrug. The carbamate-type prodrug, phototaxel 11, was stable in the dark prior to activation, whereas carbonate-type phototaxel 9 demonstrated poor stability under aqueous conditions. For such prodrugs, tumor-tissue targeting after administration could be achieved by selective light delivery, similar to that used in photodynamic therapy. In addition, newly designed coumarin derivative 8 can be applied in organic chemistry as a photosensitive protective group and for the design of caged compounds.
Noguchi
Mayo
M
Department of Medicinal Chemistry, Center for Frontier Research in Medicinal Science and 21st Century COE Program, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan.
Skwarczynski
Mariusz
M
Prakash
Halan
H
Hirota
Shun
S
Kimura
Tooru
T
Hayashi
Yoshio
Y
Kiso
Yoshiaki
Y
D002851:Chromatography, High Pressure Liquid; D003374:Coumarins / Q000138:chemical synthesis* / Q000737:chemistry / Q000528:radiation effects; D015195:Drug Design; D007834:Lasers; D008968:Molecular Conformation; D017239:Paclitaxel / Q000138:chemical synthesis* / Q000737:chemistry / Q000528:radiation effects; D010777:Photochemistry; D010782:Photolysis; D017319:Photosensitizing Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000528:radiation effects; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000528:radiation effects; D012995:Solubility; D013237:Stereoisomerism; D014466:Ultraviolet Rays; D014867:Water / Q000737:chemistry
D003374:Coumarins; D017319:Photosensitizing Agents; D011355:Prodrugs; D014867:Water; C030123:coumarin; D017239:Paclitaxel