title: Diprotonation process of meso-tetraphenylporphyrin derivatives designed for photodynamic therapy of cancers: from multivariate curve resolution to predictive QSPR modeling.
abstract: Tetrapyrrole rings possess four nitrogen atoms, two of which act as Bröndsted bases in acidic media. The two protonation steps occur on a close pH range, particularly in the case of meso-tetraphenylporphyrin (TPP) derivatives. If the cause of this phenomenon is well known--a protonation-induced distortion of the porphyrin ring--data on stepwise protonation constants and on electronic absorption spectra of monoprotonated TPPs are sparse. A multivariate approach has been systematically applied to a series of glycoconjugated and hydroxylated TPPs, potential anticancer drugs usable in Photodynamic Therapy. The dual purpose was determination of protonation constants and linking substitution with basicity. Hard-modeling version of MCR-ALS (Multivariate Curve Resolution Alternating Least Squares) has given access to spectra and distribution profile of pure components. Spectra of monoprotonated species (H(3)TPP(+)) in solution resemble those of diprotonated species (H(4)TPP(2+)), mainly differing by a slight blue-shift of bands. Overlap of H(3)TPP(+) and H(4)TPP(2+) spectra reinforces the difficulty to evidence an intermediate form only present in low relative abundance. Depending on macrocycle substitution, pK values ranged from 3.5±0.1 to 5.1±0.1 for the first protonation and from 3.2±0.2 to 4.9±0.1 for the second one. Inner nitrogens' basicity is affected by position, number and nature of peripheral substituents depending on their electrodonating character. pK values have been used to establish a predictive Multiple Linear Regression (MLR) model, relying on atom-type electrotopological indices. This model accurately describes our results and should be applied to new TPP derivatives in a drug-design perspective.
authors.affiliation: Univ. Paris-Sud, EA 4041, IFR 141, Faculté de Pharmacie, F-92296 Châtenay-Malabry, France. benoit.chauvin@u-psud.fr
authors.forename: Benoît
authors.initials: B
authors.lastname: Chauvin
authors.forename: Athena
authors.initials: A
authors.lastname: Kasselouri
authors.forename: Pierre
authors.initials: P
authors.lastname: Chaminade
authors.forename: Rita
authors.initials: R
authors.lastname: Quiameso
authors.forename: Ioannis
authors.initials: I
authors.lastname: Nicolis
authors.forename: Philippe
authors.initials: P
authors.lastname: Maillard
authors.forename: Patrice
authors.initials: P
authors.lastname: Prognon
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry*; D006801:Humans; D015999:Multivariate Analysis; D009369:Neoplasms / Q000188:drug therapy; D010778:Photochemotherapy; D056951:Photoelectron Spectroscopy / Q000379:methods; D011166:Porphyrins / Q000737:chemistry*; D011522:Protons; D021281:Quantitative Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D011166:Porphyrins; D011522:Protons; C409084:tetraphenylporphyrin