| This dissertation is mainly focused on the synthesis of some novel derivatives of amino acid, steroid and Maslinic acid via "Click Chemistry", and includes four parts:(1) A series of azide-functionalized L-serine derivatives were prepared by azide substitution of C3-OH of the protected L-serine. Meanwhile, some protected L-serine derivatives with O-alkynyl at C-3 position were also synthesized with L-serine as the raw material.(2) Ten triazole crosslinking L-amino acid derivatives 24-33, which could be used as potential protein crosslinkers, metal labels, were synthesized via click reaction of 3-azide and alkyne protected L-serine as raw material.(3) 6-aminohexanoic acid functionalized with 6-azide was prepared with a yield of 70% with protected L-lysine as the starting material and ImSO2N3 as a reagent. L-phenylalanine derivatives with azide and alkynyl groups were also synthesized with L-tyrosine and p-nitrophenylalanine as raw materials.(1) Ten fluorescent symmetrical bis-amino acids and sixteen mono-substituted amino acid derivatives were successfully prepared with click chemistry, by introducing different fluorophores (fluorescein, dansyl, NBD, coumarin and benzothiadiazole) into the side chain of serine, lysine and phenylalanine. Furthermore, asymmetrical fluorescent bis-amino acid derivatives were synthesized via step by step of click reaction.(2) The general spectroscopic properties of 56,76-79,84,92 indicated that, except for the fluorescein derivatives, spectroscopic properties of the newly synthesized fluorophores in EtOH and DMSO were similar to the native molecules which exhibited large Stokes shifts and high quantum yields. Fluorescent emission of the different compounds was affected by solvent polarity. Compound 77, which is water-soluble, was characterized by a significant red shift in water compared to DMSO (λmaxF=500 and 475 nm, respectively). Importantly, all amino acid derivatives emit fluorescence in the visible region of the spectrum.(3) The fluorescence lifetime of the benzothiadiazole substituted amino acid derivatives (76-79) in DMSO-H2O was exceeding 14 ns which is much higher than that of tryptophan, about 3 ns. Thus, compounds 76-79 are potential fluorescence probes for studying protein dynamics or molecular interactions.(4) Insight into the fluorescence properties of coumarin derivatives 100 and 101 showed that the property of 7-hydroxy coumarin-substituted amino ester 100 was very sensitive to the pH value which made this molecule a suitable pH-sensitive amino acid to probe local pH in cell compartments.(5) Compounds 70,73-75, and 77 are interesting water soluble fluorescent amino acid derivatives. We chose 74 as a model compound to get insight into the binding properties towards metal ions (Cu2+,Mg2+,Ni2+,Co2+,Mn2+,Zn2+,Cd2+,Fe2+,Pb2+,Hg2+), and found that Hg2+ and Cu2+ could significantly quenched the fluorescent intensity, which can be used as fluorescent chemical sensor.(1) A selective method has been developed for synthesis of a-methylated steroids at C-3 and C-7 positions via 1,6-conjugate addition with AlMe3 as the methylating reagent. 12 compounds were prepared and four of them are new compounds. The structures of 120 and 148 were confirmed by X-ray single crystal diffraction. (2) The methylated steroids were tested against human gastric cancer cell line MGC-803 for their in vitro cytotoxicity, by using the SRB assay method in a dose dependent way. Compounds 114 and 144 showed the most significant cytotoxic effects, with IC50 about 1μM, and compound 135 also displayed nice inhibitory potency with IC50 about 4.7μM.(3) Six glycoconjugates of their correspondingα-methylated compounds were synthesized via click reaction, and glycoconjugate 159 showed higher cytotoxic effects on human gastric cancer cell line MGC-803 than the parent steroid 149.In order to improve the water solubility of maslinic acid which can increase the possibility of medicine and bioavailability, introducing water soluble groups (amino acids, shikimic acid, glucose and maltose) to C-28 position of MA by click reaction is a better choice.(1) Triazole crosslinking MA derivatives were prepared by introducing terminal alkynyl group at C-28 position, click reaction with azide-functionalized L-serine, and deprotection.(2) Design, synthesis of shikimic acid derivatives modified with azide. Triazole crosslinking shikimic acid-MA derivative was successfully obtained by click reaction with alkyne-functionalized MA at C-28 position and then deprotection.(3) Click reaction of MA functionalized with alkyne and azide of glucose or maltose, then deprotection of the acetyl group gave the target glycoconjugate of MA.The determination of the bioactivities of these MA derivatives is still under way. |
