Mono- and bis-decylated lumazines have been synthesized and characterized. Namely, mono-decyl chain [1-decylpteridine-2,4(1,3H)-dione] and bis-decyl chain [1,3-didecylpteridine-2,4(1,3H)-dione] conjugates were synthesized by nucleophilic substitution (SN2) reactions of lumazine with 1-iododecane in N,N-dimethylformamide (DMF) solvent. Decyl chain coupling occurred at the N1 site and then the N3 site in a sequential manner, without DMF condensation. Molecular orbital (MO) calculations show a p-orbital at N1 but not N3, which along with a nucleophilicity parameter (N) analysis predict alkylation at N1 in lumazine. Only after the alkylation at N1 in 1-decylpteridine-2,4(1,3H)-dione, does a p-orbital on N3 emerge thereby reacting with a second equivalent of 1-iododecane to reach the dialkylated product [1,3-didecylpteridine-2,4(1,3H)-dione]. Data from NMR (1H, 13C, HSQC, HMBC), HPLC, TLC, UV-vis, fluorescence, and density functional theory (DFT) provide evidence for the existence of mono-decyl chain 1-decylpteridine-2,4(1,3H)-dione and bis-decyl chain 1,3-didecylpteridine-2,4(1,3H)-dione. These results differ to pterin O-alkylations (kinetic control), where N-alkylation of lumazine is preferred and then to dialkylation (thermodynamic control), with an avoidance of DMF solvent condensation. These findings add to the list of alkylation strategies for increasing sensitizer lipophilicity for use in photodynamic therapy.

Mono- and bis-alkylated lumazine sensitizers: Synthetic, molecular orbital theory, nucleophilic index, and photochemical studies

ACS Spring Meeting 2021

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