Sapphyrins are pentapyrrolic
metal-free expanded
porphyrins with potential medical use as
anticancer agents. The novel
sapphyrin derivative,
PCI-2050, functionalized with 2-[2-(2-methoxyethoxy)ethoxy]ethoxy groups to enhance solubility and a modified bipyrrole moiety was found to be more potent in inducing apoptosis than the previously described
sapphyrin PCI-2000. Because some sapphyrins may localize to
tumors, we took advantage of the intrinsic fluorescence of these compounds to develop a flow cytometry-based assay to track
sapphyrin biodistribution in
tumor-bearing mice. Ex vivo analysis of
sapphyrin-injected animals revealed that
PCI-2050 preferentially localized to
tumor, whereas
PCI-2000 distributed into normal tissues rather than
tumor.
PCI-2050 uptake in xenograft
tumor cells and resultant
tumor cell cytotoxicity was dose dependent. To investigate structure-activity relationships, we focused on
PCI-2050 and three derivatives that differ by their alkyl substituents on the bipyrrole moiety: PCI-2051, PCI-2052, and PCI-2053. Treatment of Ramos cells in culture or treatment of Ramos xenograft-bearing animals with each of the sapphyrins followed by ex vivo growth of
tumor cells revealed the same pattern of cytotoxicity:
PCI-2050 > PCI-2052 > PCI-2051 > PCI-2053. Thus, subtle changes in the alkyl substituents on the bipyrrole moiety result in significant changes in antitumor activity.
PCI-2050 displayed significant antitumor efficacy in both Ramos and RKO xenograft models without hematologic, hepatic, or renal abnormalities as assessed by complete blood counts and serum chemistries. On the basis of these findings, it is concluded that the
sapphyrin PCI-2050 warrants further evaluation as a potential
anticancer agent due to its intrinsic proapoptotic activity and
tumor localization ability.