The furan or pyran related hetero cycles play basic role in structural units of nucleic acids (NA) and polysaccharides (PS), significantly predetermining their functional specifics. Some of such properties, in great relevancy for medicine, can be imitated through mimicry of polymers synthetic. Particularly, a formation of similar cycloisomeric chains is possible in process of free-radical cyclocopolymerization of divinyl ether (DVE) and maleic anhydride (MA). The products yielded (DVEMA) of general formula [DVE(MA)-alt-MA]n become precursors for a broad family of water-soluble derivatives capable of wide spectrum of bioactivity, including induction of interferon, immune-stimulated and direct antiviral protection. In this connection, the knowledge: what is content of different heterocyclic isomers in backbone of the preparations and what their partial contributions in promotion of the certain bioactivities observed, are in great importance. Available experimental data (NMR, IR, etc.), controversial for interpretations, didn't elucidate a required estimation of the DVEMA isomerism. The current work represents an independent exploration of the problem via quantum chemistry-based analysis of kinetic (activation barriers) and thermodynamic (enthalpies) priorities in competition between variable isomerism within the chain synthesis. The system is considered in maximal range of hypothetically allowable variations of two levels for double regioselective bifurcations: there are four competitive ways, each of which involves a sequence of four type elementary reactions for a diverse-isomeric formation of chain units. A genesis of six chiral centers (62 stereoisomers permitted) per every of the four part ways was accounted in view for up to 256 isomeric variations in total. The required time-minimized but precisely accurate computations were conducted via B3LYP/6-31G(d), M06-2X/6-311+G(d), M06-2X/6-31+G(2df,p) techniques, which were preselected through model test-systems. As a result, the mechanisms, crucial points and factors for the process-permitted regulation of isomeric content of DVEMA were studied in details. The narrow enough set of most probable enantiomers within highly competitive 5-exo- and 6-endo- ring closing sub-ways was revealed. The results obtained are very actual for an adequate modeling (docking / molecular dynamics) of DVEMA derivatives in their interactions with biopolymer targets, in search for purposed advancement of current background in design and synthesis of highly effective agents for combined antiviral protection (against HIV, flu, herpes, and other infections).
Geterotsikly, rodstvennye furanu ili piranu, igraiut bazovuiu rol' v strukturnykh zven'iakh nukleinovykh kislot (NK) i polisakharidov (PS), v sushchestvennoĭ mere opredeliaia ikh funktsional'nye osobennosti. Riad takikh osobennosteĭ, imeiushchikh prakticheskoe znachenie dlia meditsiny, udaetsia imitirovat' s pomoshch'iu mimikrii polimerov sinteticheskikh. Formirovanie skhodnykh tsiklo-izomernykh struktur vozmozhno, v chastnosti, v protsesse svobodno-radikal'noĭ tsiklosopolimerizatsii divinilovogo éfira (DVÉ) i maleinovogo angidrida (MA). Obrazuiushchiesia produkty (DVÉMA) obshcheĭ formuly [DVÉ(MA)-cher-MA]n sluzhat prekursorami obshirnogo semeĭstva vodorastvorimykh proizvodnykh s shirokim spektrom biologicheskoĭ aktivnosti, vkliuchaia induktsiiu interferona, immunostimuliruiushchuiu i priamuiu protivovirusnuiu zashchitu. V sviazi s étim vazhno znat', kakovo sootnoshenie razlichnykh geterotsiklicheskikh izomerov v ostove étikh soedineniĭ i kakova ikh rol' v realizatsii tekh ili inykh vidov nabliudaemoĭ aktivnosti. Imeiushchiesia éksperimental'nye dannye (IaMR, IK i dr.), vvidu neodnoznachnosti ikh interpretatsii, ne pozvoliali priĭti k iasnoĭ otsenke izomernogo sostava DVÉMA. Poétomu v dannoĭ rabote provedeno nezavisimoe kvantovo-khimicheskoe issledovanie s analizom kineticheskikh (énergiia aktivatsii) i termodinamicheskikh (éntal'piia) prioritetov konkurentnoĭ izomerizatsii tsepi v protsesse sinteza. Rassmotrena sistema reaktsiĭ v maksimal'nom diapazone gipoteticheski dopustimykh variatsiĭ dvukh urovneĭ parno-razvetvlennoĭ regioselektivnosti: chetyre konkuriruiushchikh marshruta v posledovatel'nostiakh chetyrekh tipov élementarnykh reaktsiĭ formirovaniia zven'ev tsepi, razlichnykh po strukturnoĭ izomerii. Po kazhdomu iz marshrutov uchten poshagovyĭ genezis shesti khiral'nykh tsentrov (64 stereoizomerov) – do 256 izomernykh variatsiĭ summarno. Ékonomichnyĭ rezhim tochnykh raschetov obespechivalsia metodami B3LYP/6-31G(d), M06-2X/6-311+G(d), M06-2X/6-31+G(2df,p), proshedshimi predvaritel'nuiu selektsiiu na model'nykh test-sistemakh. V rezul'tate detal'no izuchen mekhanizm, kriticheskie tochki i faktory vozmozhnoĭ reguliatsii izomernogo sostava DVÉMA. Ustanovlen dostatochno uzkiĭ interval naibolee veroiatnykh énantiomerov v riadu vysoko konkurentnykh sub-marshrutov 5-ékzo- i 6-éndo- tsiklizatsii. Poluchennye rezul'taty neobkhodimy dlia adekvatnogo modelirovaniia (doking/molekuliarnaia dinamika) proizvodnykh DVÉMA vo vzaimodeĭstviiakh s biopolimernymi misheniami v tseliakh razvitiia imeiushchegosia zadela po dizaĭnu i sintezu vysokoéffektivnykh agentov kombinirovannoĭ protivovirusnoĭ zashchity (ot VICh, grippa, gerpesa i dr. infektsiĭ).
Keywords: DIVEMA; biological activity; cyclization; isomerism; modeling; polymerization.