A novel purine disaccharide nucleoside was isolated from the crustacean Ligia exotica and purified by HPLC on GS 320 and ODS column. By the spectral analyses of $^1H NMR$, $^{13}C NMR$, HMQC, HMBC, NOESY, HRFAB-MS and UV spectra, the new nucleoside was expected to be 3'-O-(α-D-glucosyl) inosine. The structure of natural product was unambiguously confirmed by total synthesis. Activation of the benzyl-protected gluco-pyranosyl donor 18 with $BF_3-Et_2O$ at -10℃ in the presence of acceptor 16a led to the consumption of both starting materials and formation of a glycosylated products 19 as an approximate 8:1 mixture of α and β anomers. Silica gel column separation of the anomers is readily effected after desilylation to give the α -disaccharide 20 and its β-anomer 21. The 20 was treated with $Pd(OH)_2/C$ in the presence of cyclohexene and EtOH to give compound 13 of which spectral data were all identical with those of the natural product. Thus the structure of natural product was concluded to be 3'-O-(α -D-glucosyl)inosine. The synthesis of 13 by glucosylation of a suitably protected inosine derivative under mild conditions and its various analogues have been synthesized to test biological activities. One of the synthetic derivatives exhibited cytotoxicity against human cancer cell with $GI_50$ value of 2.31㎍/ml in vitro.
In order to synthesize new quinoxaline antibiotics, cyclic octadepsipeptide 78 has been prepared from Cbz-D-Ser[BOC-Ala-MeCys(Bam)-Me-Val]-OH 72 and Cbz-D-Ser[H-Ala-MeCys(Bam)-Me-Val]-OPa 73 as a key intermediate. The protected tetradepsipeptide 71 was treated with Zn in aqueous 90% acetic acid effected reductive cleavage of the phenylacyl (Pa) ester function to provide tetradepsipeptide 72 having a free C-terminal carboxyl group. Tetradepsipeptide 73 required for fragment coupling with 72 was prepared by treatment of 71 with $TFA-CH_2Cl_2$. The coupling of 72 and 73 with DCC-HOBt in THF afforded the linear octadepsipeptide 74 in 65% yield. The compound 78 was prepared from 74 through 4 steps. A synthetic quinoxaline antibiotic (YK-2000) was prepared through 4 steps from 78. Reductive cleavage of the disulfide with ethanolic NaHSe gave dithiol. A methylene insertion reaction for construction an $S-CH_2-S$ bridge between two N-Me cysteine residue was achieved by use of TBAF-hydrate in $CH_2Cl_2$ with yield 85%. Acidolysis of the benzyloxycarbonyl group with HBr in acetic acid and acylation with 2-quinoxalyl chloride gave crude YK-2000 which is a novel quinoxaline antibiotic having a $-CH_2-S-CH_2-S-CH_2-$ bridge. The crude YK-2000 was purified by silicagel column chromatography and exhibits cytotoxicity against human cancer cell with $IC_50$ value of 2.7㎍/ml in vitro.
갑각류 해양동물인 갯강구로부터 생리활성 물질에 관한 연구를 진행하던중 새로운 퓨린계 핵산이 분리되었다. $^1H$ NMR, $^13NMR$, HMQC, HMBC, NOESY, HRFAB-MS, UV 스펙트럼등 여러가지 데이터를 분석하여 이 화합물의 구조를 3'-O-(α-D-글루코실)이노신13 으로 예상하고, 구조를 확인하기 위하여 전합성을 시도하였다. 글루코실이미데이트 15 와 $^1N-벤질$ 2',5’-디-t-부틸디메틸실릴이노신 14을 과량의 $BF_3-Et_2O$하에서 반응시켜 글리코실이노신16을 합성하였다. 이때 생성물의 입체선택성은 α:β 아노머를 약 8:1의 혼합물로 얻을수 있었으며, 이후의 탈보호화 반응을 진행시켜 두개의 아노머를 분리할수 있었다. 이중 α아노머의 모든 스펙트럼이 천연물에서 얻은 스펙트럼과 일치하였으며, 따라서 천연물의 구조를 3'-O-(α-D-글루코실)이노신으로 결정할 수 있었다. 13의 여러 유도체를 합성하여 생리활성을 실험한 결과 3'-O-(α-D-글루코실)이노신의 경우 인간의 암세포에 대한 세포독성이 2.31㎍/ml으로 나타났다.
새로운 퀴녹살린계 항생제를 합성하기 위하여 Cbz-D-Ser[BOC-Ala-MeCys(Bam)-Me-Val]-OH 72와 Cbz-D-Ser[H-Ala-MeCys (Bam)-Me-Val]-OPa 73로부터 중요중간체인 사이클릭옥타펩타이드78를 합성하였다. 테트라펩타이드 71의 C-단말보호기인 페닐아실그룹을 Zn을 이용하여 탈보호화시켜 펩타이드 2를 합성하고, N-단말보호기인 Boc그룹을 TFA를 이용하여 탈보호화시켜 펩타이드 73을 합성하였다. DCC-HOBt를 활성제로 하여 72와 73을 단위결합반응을 진행하여 선형옥타펩타이드 74를 얻는다. 74의 페닐아실 탈보호화반응, 디설파이드결합생성반응, Boc 탈보호화반응을 거친 후 EDCI-HOBt을 이용한 고리화반응은 사이클릭옥타펩타이드78을 얻을 수 있다. 합성 퀴녹살린계 항생제는 78로부터 4단계를 거쳐 합성하였다. NaHSe으로 디설파이드을 환원시켜 디타이올을 만들고, TBAF수화합물을 촉매로 타이올사이에 메틸렌을 도입시켜 두 시스테인사이에 $S-CH_2-S$ 결합을 갖게하였다. Cbz보호기를 탈보호화시킨 후 2-퀴녹살릴클로라이드로 아실레이션시켜 $-CH_2-S-CH_2-S-CH_2-$ 다리를 갖는 새로운 퀴녹살린계 항생제를 합성하였으며, 인간의 암세포에 대한 세포독성이 2.7㎍/ml $(IC_50값)$을 갖는다.
