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Impact of mono- and di-β-galactose moieties in in vitro / in vivo anticancer efficacy of pyropheophorbide-carbohydrate conjugates by photodynamic therapy

To investigate the impact of mono- and di-β-galactose moieties in tumor uptake and photodynamic therapy (PDT) efficacy, HPPH [3-(1′-hexyloxy)ethyl-3-devinylpyropheophorobide-a], the meso pyropheophorbide-a [3-ethyl-3-devinyl-pyropheophorbide-a], and the corresponding 20-benzoic acid analogs were use...

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Published in:European journal of medicinal chemistry reports 2022-08, Vol.5, p.100047, Article 100047
Main Authors: Dukh, Mykhaylo, Cacaccio, Joseph, Durrani, Farukh A., Kumar, Ishaan, Watson, Ramona, Tabaczynski, Walter A., Joshi, Penny, Missert, Joseph R., Baumann, Heinz, Pandey, Ravindra K.
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Language:English
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Summary:To investigate the impact of mono- and di-β-galactose moieties in tumor uptake and photodynamic therapy (PDT) efficacy, HPPH [3-(1′-hexyloxy)ethyl-3-devinylpyropheophorobide-a], the meso pyropheophorbide-a [3-ethyl-3-devinyl-pyropheophorbide-a], and the corresponding 20-benzoic acid analogs were used as starting materials. Reaction of the intermediates containing one or two carboxylic acid functionalities with 1-aminogalactose afforded the desired 172- or 20(4′)- mono- and 172, 20(4′)-di galactose conjugated photosensitizers (PSs) with and without a carboxylic acid group. The overall lipophilicity caused by the presence of galactose in combination with either an ethyl or (1′-hexyloxy)ethyl side chain at position-3 of the macrocycle made a significant difference in in vitro uptake by tumor cells and photoreaction upon light exposure. Interestingly, among the PSs investigated, compared to HPPH 1 the carbohydrate conjugates 2 and 11 in which β-galactose moieties are conjugated at positions 172 and 20(4′) of meso-pyro pheophorbide-a showed similar in vitro efficacy in FaDu cell lines, but in SCID mice bearing FaDu tumors (head & neck) Ps 11 gave significantly improved long-term tumor cure. [Display omitted] •Photosensitizers containing two β−galactose moieties were more effective in in vitro and in vivo anti-cancer activity.•The position of the carbohydrate moieties and the presence of ethyl vs hexyloxyethyl side chain at position-3 of the PS made a significant impact in biological efficacy.•Conjugation of galactose to PS demonstrated higher uptake in liver.
ISSN:2772-4174
2772-4174
DOI:10.1016/j.ejmcr.2022.100047