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Specific inhibition of hnRNA synthesis by 5,6-dichloro-1-β-d-ribofuranosylbenzimidazole. Requirement of a free 3′-hydroxyl group, but not 2′- or 5′-hydroxyls

1982; Elsevier BV; Volume: 697; Issue: 2 Linguagem: Inglês

10.1016/0167-4781(82)90079-3

1879-2634

E. Egyházi, A. Ossoinak, Umit Tayip, Zygmunt Kazimierczuk, David Shugar,

Radical Photochemical Reactions

Five structural analogues of 5,6-dichloro-1-β-d-ribofuranosylbenzimidazole (DRB), all with modified sugar moieties, have been examined for their inhibitory activities on RNA transcription in salivary glands of Chironomus tentans. The well-known ability of the parent DRB at 65 μ M concentration to selectively inhibit hnRNA/mRNA synthesis by approx. 90% was essentially abolished on methylation of the 3′-OH; but, at an overdose the analogue suppressed labeling of all RNA classes examined (hnRNA/mRNA, rRNA, 4–5 S RNA) by 70–80%. By contrast, the 2′-O-methyl derivative of DRB was almost as effective as DRB itself in blocking transcription of hnRNA/mRNA genes. Blocking of both the 2′ and 3′ hydroxyls (2′,3′-O-isopropylidene-DRB) completely abolished inhibitory activity, irrespective of the concentration employed. The 5′-deoxy-5′-chloro derivative of DRB was only slightly less effective than the parent DRB. An unusual aspect of the activities of 2′-O-methyl-DRB and 5′-deoxy-5′-chloro-DRB was their ability to stimulate synthesis of 4–5 S RNA by 25–45%. Also investigated was the influence of the various analogues on the rate of formation of [3H]UTP from [3H]uridine used as an RNA precursor. The rate of such formation of [3H]UTP was suppressed 2–6-fold by treatment with 2′-O-methyl or 3′-O-methyl-DRB, but was unaffected by 5′-deoxy-5′-chloro-DRB or 5,6-dichloro-1-α-d-arabinofuranosylbenzimidazole. The overall data point to the importance of a free 3′-OH in the ribose moiety of DRB for selective inhibitory activity. The α-d-arabinofuranosyl analogue, although less selective in inhibition of RNA transcription, still exhibits about 50% of the activity of DRB.