Photosensitizers Related to Purpurin-18-N-alkylimides: A Comparative in vivo Tumoricidal Ability of Ester versus Amide Functionalities Gang Zheng, a William R. Potter, a Adam Sumlin, a Thomas J. Dougherty a and Ravindra K. Pandey a,b, * a Photodynamic Therapy Center, Roswell Park Cancer Institute, Bualo, NY 14263, USA b Department of Nuclear Medicine, Roswell Park Cancer Institute, Bualo, NY 14263, USA Received 18 October 1999; accepted 12 November 1999 AbstractÐFor a comparative study, 3-(alkyloxyethyl)-3-devinylpurpurin-18-N-hexylimides with ester and amide functionalities were investigated for tumor selectivity and in vivo photosensitizing ecacy. Compared to amide analogues, the related photo- sensitizers with ester functionalities were found to be more eective. Among these compounds the 3-devinyl-(3-hexyloxyethyl)- purpurin-18-N-hexylimide as methyl ester 12 showed excellent tumor uptake (tumor versus muscle ratio: 8:1), and produced 100% tumor cure on day 30 at a dose of 1.0 mmol/kg. The mice were treated with light (135 J/cm 2 , 705 nm) at 24 h post injection of the drug. # 2000 Elsevier Science Ltd. All rights reserved. Photodynamic therapy (PDT), now a well recognized treatment for the destruction of tumors, utilizes the ability of a selectively retained photosensitizer to elicit an ecient photodynamic reaction upon activation with tissue penetrating light. 1 Photofrin, 1 a mixture of porphyrin oligomers, is currently the only PDT drug approved by the Health Agencies in the United States and elsewhere. Despite its excellent PDT ecacy, Photofrin 1 suers with several drawbacks: (a) it is a chemically complex mixture, (b) its long wavelength absorption at 630 nm lies well below the wavelength necessary for the maximum tissue penetration, and (c) it induces cutaneous prolonged photosensitivity. There- fore, during the past decade, numerous eort has been devoted in developing long wavelength absorption photosensitizers, the so called `second and third gen- eration PDT drugs' with well de®ned structures and low phototoxicity. 2 The earlier contributions from our laboratories have shown that variation of substituents in parent molecules of a variety of systems makes a signi®cant dierence in PDT biological activity. For example, in a congeneric series of alkyl ether analogues of pyropheophorbide a the in vivo photodynamic ecacy demonstrated a parabolic relationship being maximum in compounds with n-hexyl and n-heptyl chains at position-3 (ring A). 3 The structural elements evaluated in this in vivo quan- titative structure/activity relationship (QSAR) study include the length and shape (alkyl, alkenyl, cyclic, and secondary analogues) of the ether side chain. Thus, three end points including tumor growth delay, tumor cell lethality, and vascular perfusion after treatment revealed highly similar QSAR patterns that constituted a function of the alkyl ether chain length and drug lipophilicity. Recently, Dagan and co-workers 4 reported in vitro photodynamic ecacy of a series of pheophorbide a derivatives in which the carboxylic acid group of the 17-propionic acid functionality was replaced by alkyl amide substituents with variable carbon numbers and terminal groups. Optimal photosensitizer uptake in cells and photosensitizing activity were observed with com- pounds containing side-chain lengths of 4±6 carbon units with -OH and -CH 3 terminal ends. The most eective compound, the N-(4-hydroxybutyl)amide deri- vative, was found to be more eective than Photofrin 1 in vitro. Unfortunately, there is no report regarding their in vivo studies. 0960-894X/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved. PII: S0960-894X(99)00649-6 Bioorganic & Medicinal Chemistry Letters 10 (2000) 123±127 *Corresponding author. Tel.: +1-716-845-3203; fax: +1-716-845- 8920; e-mail: rpandey@sc3103.med.bualo.edu