Design, synthesis, and biological evaluation of novel derivatives of dithiodiglycolic acid prepared via oxidative coupling of thiols.

Human thioredoxin reductase 1 (TrxR1) is a selenocysteine-containing enzyme which plays a crucial role in regulating numerous redox signalling pathways within the cell. While its functioning is important in all cells, levels of TrxR1 expression are higher in cancer cells, possibly as an adaptation to much higher levels of reactive oxygen species and the need for more extensive DNA synthesis. This makes TrxR1 an attractive target for cancer therapy development. Inspired by the structure of disulphide compounds which have advanced through various stages of clinical development, we designed a series of dithiodiglycolic acid derivatives. These were prepared from respective thiol synthons using an iodine- or benzotriazolyl chloride-promoted oxidative disulphide bond formation. Inhibition of TrxR present in cell lysates from human neuroblastoma cells (SH-SY5Y) and rat liver cells indicated several compounds with a potential for TrxR inhibition. Some of these compounds were also tested for growth inhibition against two human cancer cell lines and normal human keratinocytes

Determining role of selenium in the structure - antitumor activity studies

Elektroniskā versija nesatur pielikumusPēdējā gadsimta laikā pieaugot apkārtējās vides piesārņojumam, cilvēki arvien biežāk savā ikdienas dzīvē nonāk saskarē ar kaitīgām un potenciāli kancerogēnām vielām, kā rezultātā pieaug saslimstība ar vēzi. Nākotnē ir nepieciešami selektīvi pretvēža preparāti ar pēc iespējas mazākiem blakus efektiem. Selēns ir viens no unikāliem un neaizvietojamiem mikroelementiem cilvēka veselībai. Ir noteikta savstarpēja sakarība starp selēna līmeni ikdienas uzturā un risku saslimt ar dažāda veida audzējiem, kā arī, notiek sekmīga tā izmantošana dažu vēža formu ārstēšanā. Darba galvenais mērķis ir veikt selēnu saturošo savienojumu struktūras – pretvēža aktivitātes pētījumus, lai padziļinātu zināšanas un iegūtu pilnīgāku informāciju par šo savienojumu darbības mehānismiem. Iegūtās zināšanas ļaus radīt jaunus perspektīvus selēnu saturošus pretvēža aģentus, kas spētu nomākt audzēju augšanu vai novērst tā veidošanos. Darbā ir veikti struktūras – pretvēža aktivitātes pētījumi neorganisko un organisko selēnu saturošo savienojumu klasēs. Starp pārbaudītiem organiskā amonija selenītiem ir atklāti perspektīvi pretvēža aģenti ar spēju nomākt peļu sarkomas S-180 augšanu. Salīdzinājumā ar plaši izmantoto toksisko nātrija selenītu, kā selēna avotu vairākos uztura bagātinātājos un vitamīnu kompleksos, jaunos organiskā amonija hidroselenītus var izvirzīt par audzēju profilakses līdzekļiem salīdzinošās devās kā nātrija selenītu. 1,2,3-Selēndiazola savienojumu klasē atrastie aktīvie atvasinājumi spēj nomākt audzēja augšanu in vivo un ir ar nelieliem toksiskiem blakusefektiem. Selēnazolīnija sāļu klasē tika atrasti savienojumi ar izteiktu antiproliferatīvo spēju uz audzēju šūnām in vitro. Viens no selēnazolīnija sāļiem ir 1270 reizes efektīvāks uz hepatomas MG-22A, nekā nātrija selenīts. Savienojumu augstā aktivitāte un izcilā šķīdība, salīdzinot ar Ebselēnu, ļauj pretendēt uz potenciālu pretvēža aģenta atklājumu. Izpētīti kondensēto selenofēnhinolonu un selenofēnkumarīnu antiproliferatīvā efekta darbības mehānismi uz ļaundabīgām un normālām šūnām. Viens no iespējamajiem antiproliferatīvā efekta mehānismiem ir saistīts ar apoptozes indukciju audzēju šūnās – process norit caur iniciējošās kaspāzes-2 un efektorās kaspāzes-7 aktivāciju, kā arī ekstremālu skābekļa aktīvo formu līmeņa samazināšanos šūnās. Promocijas darbā iegūtie rezultāti dod iespēju secināt, ka selēna atoma ievadīšana mērķmolekulās ļauj iegūt perspektīvus līdzekļus audzēju ārstēšanai un prevencijai.In the 20th and 21st centuries, due to environmental pollution, people more often get involved into contact with harmful and potentially carcinogenic substances that increase the risk of cancer. In the future, selective anticancer agents with the least side effects will be required. Selenium is one of the unique and essential trace elements to human health. There is a definite relationship between the level of selenium in the daily diet and the risk of developing various types of cancers; this element could additionally be used against some forms of cancer. The main goal of thesis is to study structure-anticancer activity of selenium compounds so as to acquire more complete and accurate information on the mechanisms of their action. Knowledge gained through the present study is to bring a new perspective on selenium-containing anticancer agents with the ability to inhibit tumor growth or prevent its formation. The work consists of structure-anticancer activity studies of both inorganic and organic selenium compounds classes. Among the tested organoammonium selenites, promising anti-cancer agents with the ability to inhibit murine sarcoma S-180 growth were found. Compared to the widely used toxic sodium selenite as a source of selenium, which is widely used in food supplements and vitamin complexes, new more effective organoammonium hydroselenites is proposed to be used for cancer prevention in doses comparable to sodium selenite. Active representatives in the series of 1,2,3-selenadiazole derivatives are characterized with the ability to inhibit tumor growth in vivo and less toxic side effects. Selenazolinium salts exhibit, also in vitro, antiproliferative activity against malignant cells. One of these compounds turned out to be 1270 times more effective on mice hepatoma MG-22A cell line than sodium selenite. The high activity and excellent solubility compared to Ebselen make selenazolinium salts eligible for the discovery of potential anticancer agent. Cytotoxicity and mechanisms of action of selenophenoquinolinones and selenophenocoumarins on tumor and normal cell lines were studied. One of the possible mechanisms of antiproliferative effects is associated with the induction of apoptosis in tumor cells by initiation of caspase-2 and caspase-7 activation, as well as suppression of extreme levels of reactive oxygen species in cells. Research results lead to the conclusion that the introduction of selenium atom into inorganic and organic molecules allows to obtain promising agents for the cancer treatment and prevention

Stirilpiridīnija grupu satrošu 1,4-dihidropiridīna atvasinājumu sintēze un īpašību izpēte

1,4-DHP atvasinājumi uzrāda dažādas farmakoloģiskas aktivitātes, piemēram, kardiovaskulāro, neiroprotektīvo, antiradikālo un citas. Veikt jaunu 1,4-DHP atvasinājmu sintēzi, variējot stirilpiridīnija aizvietotājus, pētīt iegūto savienojumu struktūras izmaiņu ietekmi uz to ķīmiskajām, fizikālajām un bioķīmiskajām īpašībām

Stirilpiridīia grp satrošu 1,4-dihidropiridīna atvasinājumu sintēze un īpašību izpēte

Jaunu stirilpiridīnija grupu saturošu 1,4-DHP atvasinājumu sintēze, savienojumu struktūras ietekme uz ķīmiskajām, fizikālajām īpašībām.

Novel electrophilic amides amenable by the Ugi reaction perturb thioredoxin system via thioredoxin reductase 1 (TrxR1) inhibition: Identification of DVD-445 as a new lead compound for anticancer therapy.

A series of peptidomimetic compounds incorporating an electrophilic moiety was synthesized using the Ugi reaction. These compounds (termed the Ugi Michael acceptors or UMAs) were designed to target the selenocysteine catalytic residue of thioredoxin reductase 1 (TrxR1), a promising cancer target. The compounds were assessed for their potential to inhibit TrxR1 using human neuroblastoma (SH-SY5Y) cell lysate. Based on this initial screening, six compounds were selected for testing against recombinant rat TrxR1 and in the insulin assay to reveal low-micromolar to submicromolar potency of these inhibitors. The same frontrunner compounds were evaluated for their ability to exert antiproliferative activity and induce cell death and this activity was compared to the UMA effects on the levels of reactive oxygen and nitrogen species (RONS). Collectively, the UMA compounds class presented itself as a rich source of leads for TrxR1 inhibitor discovery for anticancer application. Compound 7 (DVD-445) was nominated a lead for further optimization

Development of potent microtubule targeting agent by structural simplification of natural diazonamide

74 p.-6 fig.-4 tab.-1 tab. cont.graph.-+255 p.supp.inf.The marine metabolite diazonamide A exerts low nanomolar cytotoxicity against a range of tumor cell lines; however, its highly complex molecular architecture undermines the therapeutic potential of the natural product. We demonstrate that truncation of heteroaromatic macrocycle in natural diazonamide A, combined with the replacement of the challenging-to-synthesize tetracyclic hemiaminal subunit by oxindole moiety leads to considerably less complex analogues with improved drug-like properties and nanomolar antiproliferative potency. The structurally simplified macrocycles are accessible in 12 steps from readily available indolin-2-one and tert-leucine with excellent diastereoselectivity (99:1 dr) in the key macrocyclization step. The most potent macrocycle acts as a tubulin assembly inhibitor and exerts similar effects on A2058 cell cycle progression and induction of apoptosis as does marketed microtubule-targeting agent vinorelbine.This work was supported by ERDF (Grants 1.1.1.1/16/A/281 and KC-PI-2020/16). V.V. is grateful to MikroTik Ltd. and the University of Latvia Foundation for doctoral scholarship. R.A. and N.K. thank the support from Estonian Reaserch Council (Grant PRG399) and J.F.D. acknowledges the support from Ministerio de Ciencia e Innovación (Grant PID2022-136765OB-I00).Peer reviewe