Synthesis and antiviral activities of new acyclic and “double-headed” nucleoside analogues

Abstract

To develop an understanding of the structure-activity relationships for the inhibition of orthopoxviruses by nucleoside analogues, a variety of novel chemical entities were synthesized. These included a series of pyrimidine 5-hypermodified acyclic nucleoside analogues based upon recently discovered new leads, and some previously unknown "double-headed" or "abbreviated" nucleosides. None of the synthetic products possessed significant activity against two representative orthopoxviruses; namely, vaccinia virus and cowpox virus. They were also devoid of significant activity against a battery of other DNA and RNA viruses. So far as the results with the orthopoxviruses and herpes viruses, the results may point to the necessity for nucleoside analogues 5'-phosphorylation for antiviral efficacy.

Double-headed nucleosides: Synthesis and applications

“…Torrence and co-workers [11] synthesized triazolophthalazinesubstituted double-headed nucleosides 66a-c from uridine/ adenosine-5′-carboxylic acids 65a-c which in turn were prepared through the (2,2,6,6-tetramethylpiperidin-1-oxyl) (TEMPO) and 1,1-bis(acetoxy)iodobenzene (BAIB)-assisted oxidation of the 5′-hydroxymethylene group in adenosine/ uridine by following the methodology developed by Epp and Widlanski [53]. The nucleoside-5′-carboxylic acids 65a-c were reacted with 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) as coupling reagent followed by reaction with phthalazin-1-ylhydrazin hydrochloride in DMF in the presence of diisopropylethylamine (DIPEA) as base to afford the double-headed nucleosides 66a-c (Scheme 15) [11]. Herdewijn and co-workers [54] synthesized the double-headed nucleoside monomers 4′-C-((N 6 -benzoyladenin-9yl)methyl)thymidine ( 75) and 4′-C-((thymin-1-yl)methyl)thymidine (77) starting from 3′-O-(tert-butyldimethylsilyl)-4′-(hydroxymethyl)thymidine ( 72) which was conveniently synthesized from thymidine in five steps as reported in the literature [54][55][56].…”

“…Torrence and co-workers [ 11 ] synthesized triazolophthalazine-substituted double-headed nucleosides 66a–c from uridine/adenosine-5′-carboxylic acids 65a–c which in turn were prepared through the (2,2,6,6-tetramethylpiperidin-1-oxyl) (TEMPO) and 1,1-bis(acetoxy)iodobenzene (BAIB)-assisted oxidation of the 5′-hydroxymethylene group in adenosine/uridine by following the methodology developed by Epp and Widlanski [ 53 ]. The nucleoside-5′-carboxylic acids 65a–c were reacted with 2-(1 H -7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) as coupling reagent followed by reaction with phthalazin-1-ylhydrazin hydrochloride in DMF in the presence of diisopropylethylamine (DIPEA) as base to afford the double-headed nucleosides 66a–c ( Scheme 15 ) [ 11 ].…”

“…On the other hand, a variety of heterocyclic/carbocyclic moieties were considered as the head of these modified nucleosides. The heterocyclic structures which were found to be attached to these double-headed nucleosides include triazolophthalazine [11], 4,6-di-tert-butylbenzoxazole [12], mesitylisoxazole [13], 5-trimethylsilyl-1,2,3-triazole [14], 1-pivaloyloxymethyl-1H-1,2,3-triazole [15], 1,3,4-oxadiazino [6,5-b]indole [16], 6,7-dihydro-6-oxo-5H-1,2,4triazolo [3,4-b][1, 3,4]thiadiazine [17], 1,2,4-triazino [5,6b]indole [18], 1,3,4-thiadiazoline [19], 1,3,4-oxadiazoline [19], 1,2,4-triazoline [19], 3-mercapto-1H-1,2,4-triazole [20], 1,3,4oxadiazole-2(3H)-thione [20], 4-amino-5-mercapto-4H-1,2,4triazole [20], and 1,2,4-triazolo [3,4-b](1,3,4)-thiadiazole moieties [21]. Additionally, selected examples of doubleheaded nucleosides comprising aromatic/polyaromatic/carbocyclic moieties such as phenyl [13][14][15]22], pyrene [23][24][25], adamant-1-yl [24], cholesteryl [24], perylen-3-yl [24], 4-(tertbutyldimethylsilyloxy/hydroxy)phenyl [26], 3/4-(N-((dimethylamino)methy-lidene)aminosulfonyl)phenyl [26,27], and sulfonamido-substituted benzothiazole [28] attached as an additional head are also reported in this review article.…”

“…Triazolyl double-headed nucleosides showed efficacy against eosinophil-derived neurotoxin, which is an eosinophil secretion protein and a member of the Ribonuclease A (RNase A) superfamily [ 36 ]. Double-headed nucleosides were also found to be active against orthopox viruses, vaccinia virus, and cowpox virus under in vitro conditions [ 11 ], whereas few double-headed nucleoside analogues showed a moderate cytostatic activity against human cervix carcinoma HeLa cells [ 37 ].…”