title: Novel boronated chlorin e6-based photosensitizers: synthesis, binding to albumin and antitumour efficacy.
abstract: Chlorins, a class of plant porphyrins, are perspective as photosensitizing agents due to light absorption in the long wavelength spectral region and deeper photodamage of tissues. Aiming at optimization of antitumour properties of chlorins, we synthesized a series of boronated derivatives of chlorin e(6) and their complexes containing Zn(II), Pd(II) or Sn(IV). The compounds were synthesized by alkylation of amino or hydroxy derivatives of chlorin e(6) with 1-trifluoromethanesulfonylmethyl-o-carborane. Chlorin e(6) 13(1)-N-{2-[N-(o-carboran-1-yl)methyl]aminoethyl}amide-15(2), 17(3)-dimethyl ester (compound 5) formed complexes with serum albumin, a major porphyrin carrier. The binding constant of these complexes was approximately 4 times bigger than the respective value for the complexes of albumin with boron-free aminochlorin e(6). Compound 5 potently sensitized rat fibroblasts to illumination with monochromatic red light: >98% of cells were necrotic by 24h post-illumination with 1 microM of 5. This compound demonstrated high efficacy in photodynamic therapy of rat M-1 sarcoma. After PDT with 25mg/kg of 5 the residual tumours were significantly smaller than in animals subjected to PDT with equal concentration of boron-free aminochlorin e(6). No signs of general toxicity were detectable after PDT with 5. Thus, boronation can enhance the potency of chlorins in PDT, in particular, due to an increased binding to albumin. Our data expand the therapeutic applicability of boronated chlorins beyond boron neutron capture therapy; these agents emerge as dual efficacy photoradiosensitizers.
authors.affiliation: A.N. Nesmeyanov Institute of Organoelement Compounds, 28 Vavilov Street, 119991 Moscow, Russia. olshevsk@ineos.ac.ru
authors.forename: Valentina A
authors.initials: VA
authors.lastname: Ol'shevskaya
authors.forename: Roza G
authors.initials: RG
authors.lastname: Nikitina
authors.forename: Arina N
authors.initials: AN
authors.lastname: Savchenko
authors.forename: Marina V
authors.initials: MV
authors.lastname: Malshakova
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Vinogradov
authors.forename: Galina V
authors.initials: GV
authors.lastname: Golovina
authors.forename: Dmitry V
authors.initials: DV
authors.lastname: Belykh
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Kutchin
authors.forename: Mikhail A
authors.initials: MA
authors.lastname: Kaplan
authors.forename: Valery N
authors.initials: VN
authors.lastname: Kalinin
authors.forename: Vladimir A
authors.initials: VA
authors.lastname: Kuzmin
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Shtil
mesh_terms: D000418:Albumins / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001895:Boron / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D002735:Chlorophyllides; D006801:Humans; D017319:Photosensitizing Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011166:Porphyrins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D014226:Triazenes / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000418:Albumins; D000970:Antineoplastic Agents; D002735:Chlorophyllides; D017319:Photosensitizing Agents; D011166:Porphyrins; D014226:Triazenes; C062985:phytochlorin; C008848:1-phenyl-3,3-dimethyltriazene; D001895:Boron