Synthesis of certain linear tricyclic nucleosides as potential antineoplastic agents
Creators: name: Chung, Fung-Lung
Publisher: name: University of Utah
Year: 2012
Subjects: Debromination
Carbonyl Sulfide

description: The discovery of a naturally-occurring fluorescent nucleoside in t-RNA[phe] of yeast in 1967 was followed by the identification of its structure as a ribonucleoside possessing a linear tricyclic aglycon, the Y base.  This structural assignment has generated considerable interest in the design and synthesis of various tricyclic nucleosides. In addition, the observations that certain tricyclic nucleoside analogs (I and II) displayed significant in vivo antitumor activity has prompted this study in which a new class of tricyclic nucleosides possessing a [6:5:6] linear aglycon has been synthesized.  4,5-Diamino-9- (beta-D-ribofuranosyl) pyrimido [5,4-f] pyrrolo [2,3-d]-pyrimidine (III), an adenosine-adenosine analog, has been prepared from 6-aminotoyocamycin (VI) using three different synthetic routes. 4,7-Diaoino-9- (beta-D-ribofuranosyl) pyrimido [5,4-f] pyrrolo [2,3-d] pyrimidin-5-one (IX), an adenosine-guanosine analog, and several adenosine-6-mercaptopurine ribonucleoside type tricyclic nucleoside derivatives have also been synthesized.  The synthesis of 4-amino-9-(beta-D-ribofuranosyl) pyrimido [5,4-fJpyrrolo[2,3-dJ pyrimidin-5-one (XXVII), an adenosine-inosine analog, and 4-amino-9-(S-£-ribofuranosyl)pyrimido[5,4-f]pyrrolo-[2,3-d] pyrimidin-5-one (XXVIII), an adenosine-xanthosine analog, have been achieved.  Structural assignments have been based on pmr spectral studies as well as an unequivocal chemical proof of structure. An interesting chemical shift for the 2'-hydrogen of certain tricyclic nucleosides prepared in this study was observed and is discussed. The in vitro cytotoxicity of these nucleosides against leukemia L-1210 has been determined.  The in vivo evaluation of these tricyclic nucleosides against mouse leukemia will also be discussed.  A facile synthesis of the new linear" tricyclic nucleoside, 4, 5-diamino-9-(beta-D-ribofuranosyl)pyrimido[5,4-f]pyrrolo[2,3-d] pyrimidin-7-one (XXXVII), an analog of both adenosine and isoguanosine has been accomplished using an appropriately substituted pyrrolo[2,3-d] pyrimidine nucleoside as starting material.  A key reaction in this synthesis involves the ring-closure of an o-aminonitrile with the novel reagent carbonyl sulfide (COS).  This ring-closing reaction using 6-aminotoyo-camycin (VI) as starting material furnished 4-amino-9-(beta-D-ribofuranosyl)-pyrimido[5,4-f]pyrrolo[2,3-d] pyrimidin-7-one-5-thione (XXXIV) in good yield.  The use of carbonyl sulfide as a ring-closing reagent appears to be general for the synthesis of fused pyrimidin-one-thione derivatives from o-aminonitrile compounds.  The synthesis of 4-amino-9-(beta-D-ribofuranosyl)-v-triazino[5,4-f]-pyrrolo[2,3-d]pyrimidin-5-one (XLII), a derivative of anew linear tricyclic heterocyclic ring system was achieved by selective diazotization of the exocyclic-amino group in the 6-position of 6-aminosangiva-mycin (VIII).  In an attempt to synthesize the corresponding 5-chloro derivative, we have observed an unusual ring-opening reaction.  The isolation and identification of this ring-opened product has provided some insight into the mechanism of this ring-opening reaction. Finally, in an attempt to synthesize 6-fluorotoyocamycxn (LII)from 6-bromotoyocamycin (V) via a displacement of the 6-bromo atom by a fluoride ion using N,O-bis(trimethylsilyl)acetamide (BSA), potassium fluoride and dicyclohexyl-18-crown-6, an unexpected reductive debromination reaction was observed.  This reductive debromination reaction was also observed for certain other purine type nucleosides, BSA and potassium fluoride have been found to be indispensable for this debromination reaction.