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6-Morpholino- and 6-amino-9-sulfonylpurine derivatives. Synthesis, computational analysis, and biological activity

Matić, Josipa; Jukić, Marijana; Ismaili, Hamit; Saftić, Dijana; Ban, Željka; Tandarić, Tana; Vianello, Robert; Opačak-Bernardi, Teuta; Glavaš-Obrovac, Ljubica; Žinić, Biserka (2021) 6-Morpholino- and 6-amino-9-sulfonylpurine derivatives. Synthesis, computational analysis, and biological activity. Nucleosides, Nucleotides and Nucleic Acids, 40 (4). pp. 470-503. ISSN 1532-2335

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The synthesis of novel 6-chloro/morpholino/amino/-9-sulfonylpurine derivatives was accomplished in two ways, either (i) involving the condensation reaction of 6-chloropurine with commercially available arylsulfonyl chlorides in acetone and the presence of aqueous KOH at 0 °C, followed by the substitution of C6-chlorine with morpholine, or (ii) employing a reversed synthetic approach where 6-morpholinopurine and commercially available adenine bases were reacted with the corresponding alkyl, 2-arylethene and arylsulfonyl chlorides giving the N9 sulfonylated products, the latter particularly used where prior nonselective sulfonylation was observed. In both approaches, the sulfonylation reaction occurred regioselectively at the purine N9 position lacking any concurrent N7 derivatives, except in the case of a smaller methyl substituent on SO2 and the free amino group at C6 of the purine ring. The tautomeric features of initial N9 unsubstituted purines, as well as stability trends among the prepared N-9-sulfonylpurine derivates, were investigated using DFT calculations with an important conclusion that electron-donating C6 substituents are beneficial for the synthesis as they both promote the predominance of the desired N9 tautomers and help to assure the stability of the final products. The newly synthesized 6-morpholino and 6-amino-9-sulfonylpurine derivatives showed antiproliferative activity on human carcinoma, lymphoma, and leukemia cells. Among the tested compounds, 6-morpholino 17 and 6-amino 22 derivatives, with trans-β-styrenesulfonyl group attached at the N9 position of purine, proved to be the most effective antiproliferative agents, causing accumulation of leukemia cells in subG0 cell cycle phase.

Item Type: Article
Uncontrolled Keywords: 6-Chloropurine, 6-morpholinopurine, adenine, regioselective N-9-sulfonylation, DFT calculations, biological activity
NATURAL SCIENCES > Chemistry > Organic Chemistry
Divisions: Division of Organic Chemistry and Biochemistry
Project titleProject leaderProject codeProject type
Sinteza novih biološki aktivnih derivata nukleobaza i nukleotida-Biserka Žinić098-0982914-2935MZOS
Višenamjensko očitavanje DNA/RNA sekundarne strukture molekularnim kemijskim senzorima-DNA/RNA-MolSenseIvo PiantanidaIP-2013-11-1477HRZZ
Depositing User: Dijana Pavlović Saftić
Date Deposited: 02 Sep 2022 13:28
DOI: 10.1080/15257770.2021.1896001

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