Purine and 1-deazapurine ribonucleosides and deoxyribonucleosides: synthesis and biological activity

Abstract

A series of 6-(hydroxylamino)purine and -1-deazapurine nucleosides were synthesized and tested for their antitumor and adenosine deaminase inhibitory activity. All the examined molecules displayed an in vitro activity comparable to that of the reference compounds 6-(hydroxylamino)-9-beta-D-ribofuranosylpurine (HAPR) and ara-A, their ID50 ranging from 0.9 microM to approximately 100 microM. The 6-hydroxylamino derivatives of 1-deazapurine 9, 12, and 17 and also the blocked compound 13 are inhibitors of ADA whereas the purine derivatives 4 and 6 and the nitro compounds 11 and 16 are resistant to the enzyme. 7-(Hydroxylamino)-3-(2-deoxy-beta-D-erythro-pentofuranosyl)-3H-imi dazo[4,5- b]pyridine, the less cytotoxic but the most active ADA inhibitor in the series (Ki = 2.7 x 10(-7)), greatly potentiates the antitumor activity of ara-A in vitro.

Synthesis of 6‐Substituted 1‐Deazapurine 2′‐Deoxyribonucleosides

“…of compound 6a did not agree with literature data (see Exper. Part), a full set of analytical data was collected which confirmed the structure already reported [8].…”

“…~ The 1-deazapurine nucleosides, such as l-deaza-2'-deoxyadenosine (la) [l] [2] (purine numbering is used throughout the General Part) or the ribonucleoside lb [3] [4] can form Hoogsteen base pairs within oligonucleotide duplexes [2] [5]. The synthesis of 1 -deazapurine deoxyribonucleosides can be performed by i) deoxygenation of ribonucleosides [l], ii) the microbial transglycosylation of imidazo [4,5-b]pyridine bases [6] [7], and iii) the stereoselective glycosylation of the nucleobases with sugar halides [8] [9]. In the following, we report on the nucleobase-anion glycosylation of 6-substituted 1-deazapurines and their conversion into the nucleosides 2a-d or 3a-d.…”

The Pivotal Role of the Mitochondrial Amidoxime Reducing Component 2 in Protecting Human Cells against Apoptotic Effects of the Base Analog N6-Hydroxylaminopurine

“…The N-hydroxylated nucleoside HAPR however, was very efficiently metabolized to inosine and not as expected to the corresponding nucleoside adenosine. In accordance to our findings, it is described that adenosine but also HAPR is quickly broken down to inosine in organisms (39,40). It is known that this deamination of adenosine is catalyzed by adenosine deaminase (41).…”

“…It is known that adenosine has a short half-life in vivo as it is easily deaminated to inosine by adenosine deaminase (39,40). Therefore, adenosine as an intermediate might not be detectable in the detoxication pathway of HAPR.…”

Synthesis of 3H-imidazo[4,5-b] pyridine with evaluation of their anticancer and antimicrobial activity

“…The medicinal properties of pyridine include a variety of pharmacological applications, such as antibacterial [19], antiparacite [20], antitumor [21], anticancer [22,23], antiviral [24] and anti-inflammatory [25]. In addition, they can act as antagonists of various biological receptors [26].…”