To enlarge a spectrum of biologically active compounds in the series of the 1,2,4-triazino[5,6-b] [1,4]benzothiazine (1,2,4-TBT) derivatives and reveal among them efficient inhibitors of RNA synthesis Methods. The methods of structure optimization of the 3-oxo-1,2,4-TBT by fragment-oriented substitution, the molecular doking of new structures in a virtual target, the rational chemical synthesis of the theoretically predicted compounds and their testing in the system of transcription in vitro. Results. The series of 1,2,4-TBT derivatives with substituents in the benzene and triazine cycles of a base molecule were synthesized. The testing of synthesized compounds in the in vitro transcription system directed by T7 RNA polymerase revealed the structure-and concentration dependent inhibition of the RNA synthesis by some of these compounds. The experimental and virtual screening data for all investigated compounds have a good correlation. It was found that most effective derivative is the 3-oxo-8-butyl-1,2,4-TBT which completely inhibited transcription at the concentration of 6 mg/ml. Conclusions. The biotesting results allow us to assume that the inhibition of RNA synthesis is caused by binding of the 3-oxo-8-butyl-1,2,4-TBT to both free RNA polymerase molecules and those including in a transcriptional complex with DNA.
Інститут молекулярної біології та генетики НАН України 252143, Київ, вул. Академіка Заболотного, 150 В огляді наведено дані власних робіт з вивчення поліну клеотид них інгібіторів вірусної репродукції. На моделях ДНК-та РНК-геномних вірусів показано противірусну активність ряду нуклеїнових кислот з різних природних джерел, а їхні алкіловані похідні виявилися значно ефективнішими інгібіторами вірусної репродукції. Ендогенний синтез антисенсових РНК забезпечував суттєве пригнічення репродукції В1Л-1 у культурах гемопоетичних клітин людини. Синтезовано та клоновано рибозим, здатний специфічно розрізати in vitro tat-PHK ВІЛ-J.
In sti tute of mo lec u lar bi ol ogy and ge net ics NAS of Ukraine Academicain Zabolotnog str., 150, Kyiv, 03680 Ukraine shved_@ imbg.org. ua De sign and syn the sis of a set of 3,5-dioxy-1,2,4-triazinyl-6-propionic acid (TPA) arylamides were de veloped in or der to search for new com pounds with fungistatic prop er ties on the ba sis of azapyrimidine de riv atives. Carboxamides ca pa ble to block tran scrip tion were re vealed among ob tained com pounds us ing T7 RNA-pol model test-sys tem in vi tro, and the only de riv a tives con tain ing halogene-substituent in pharmacophore part showed the in hib i tory prop er ties. The model of vir tual tri ple non-pro duc tive com plex at poly mer ase cat a lytic site (in hib i tor-en zyme-DNA tem plate) was pro posed, il lus trat ing a pos si ble mech anism of in hib i tory ac tion of such com pounds on RNA syn the sis. Pre lim i nary screen ing of new triazine de riva tives re vealed their in hib i tory ac tion against some kinds of fungi and bac te ria.Keywords: 1,2,4-triazine de riv a tives, syn the sis, sup pres sion of tran scrip tion, T7 RNA-pol, antifungal ac tivity.
441ISSN 0233-7657. Biopolymers and cell. 2007. vol. 23. N 5. Translated from Ukrainian.
Aim.To evaluate a series of 2-substituted thiazolo [3,2-a]benzimidazolones as potential transcription inhibitors. Methods. Compounds were tested in a model transcription system based on T7 RNA polymerase. Results. The testing revealed a number of compounds able to inhibit transcription at micromolar concentrations. The most active inhibitor was dihydroxy derivative BT29 with IC 50 = 1.6 mM. Conclusions. Structure-functional dependence of the activity of tested compounds as transcription inhibitors was found.The key structural feature required for their high activity is a presence of hydroxy or dialkylamino group at p-or m-position of arylidene fragment.
Сконструйовано та синтезовано низку композитів на основі похідних феназин-1-карбонової кислоти та 6-азаураиилу, будову яких підтверджено методами УФ та 1 Н-ЯМР спектроскопії. Неемпіричний (ab initio) квантовохімічний конформаційний аналіз на рівні теорії HF/6-3JG* висвітлив функціонально важливі особливості просторової будови отриманих композитів: у залежності від положення, довжини та складу лінкера, який з'єднує домени, утворюються компактні або розрихлені «складені» структури, що по-різному впливають на. роботу полімеразного комплексу.
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