Synthesis of novel bioconjugates of α-tocopherol with lupane triterpenoids

Abstract

The first representatives of α tocopherol bioconjugates with lupane triterpenoids were synthesized using amino acid residues and dipeptides as linkers between the antioxidant mole cule and the terpenoid C(28) atom. The synthetic combination of natural compounds was carried out by the reaction of lupane acid chlorides (betulonic and betulinic acid chlorides) with amino acid and dipeptide derivatives of α tocopherol.Currently, bioconjugates of natural compounds or hy brid molecules combined from pharmacophores of native and synthetic biologically active compounds are used most often in the development of new polyfunctional pharma ceutical agents in combinatorial and medical chemistry. 1 Interesting results along this line were obtained by involv ing the lipophilic antioxiodant α tocopherol (Vitamin Е) and related chromanols in combinations with other mole cules. Thus by modification of known camptotecin and taxol based antitumor agents by α tocopherol, the prob lems related to poor solubility of these agents in fats were solved, their lipophilicity and retention in membranes in creased and, as a consequence, a higher therapeutic effi ciency was attained. 2,3 The previously prepared 4 α toco pherol conjugates with 5 aminolevulinic acid are of inter est for the photodynamic therapy. Heterodimers based on available water soluble chromanol, the Trolox acid, be haved as multifunctional agents exhibiting high anti oxiodant, 5 antitumor, 6 antiinflammatory, 7 and antiar rhythmic activities. 8 No data on bioconjugates of α tocopherol with lu pane triterpenoids can be found in the literature, al though a combination of the potent lipophilic antioxiodant with lupane terpenoids having diverse biological acti vities 9,10 could lead to mutual synergistic influence of the combined molecules or new valuable biological acti vity of the hybrid compound. In the preliminary com munication, 11 we reported the synthesis of α tocopherol conjugate with betulonic acid with glycine residue as the spacer. Here we synthesized a number of structurally related hybrids of α tocopherol and lupane acids conju gated by L amino acids and dipeptides through amide and ester bonds. Results and DiscussionThe target conjugates were synthesized by acylation of α tocopherol (1) with N benzyloxycarbonyl derivative of glycine (2a), L valine (2b), L phenylalanine (2c), or L lysine (2d) in the presence of DCC and DMAP. The amino group in the synthesized О acyl derivatives 3a-d was deprotected by hydrogenolysis in the presence of a palladium catalyst. The obtained conjugates 4a-d with free amino group were converted into oxalates 5a-d sta ble on storage by adding a specified amount of oxalic acid to the reaction medium during the removal of the benzyl oxycarbonyl (Сbz) protecting group (Scheme 1). In the 1 H NMR spectra of salts 5a-d, the signals of protons at the carbon atoms connected to nitrogen are shifted down field (Δδ ≈ 0.6-0.9), whereas the 13 С NMR spectra of oxalates show upfield (Δδ ≈ 5) shifts for the signals of carbonyl C atoms with respect to the...