Sinteza heterocikličkih derivata ferocena s potencijalnim citostatskim djelovanjem

master's thesis

• Title (english): Synthesis of heterocycle derivatives of ferrocene with potential cytostatic activity
• Author: Helena Šimek
• Mentor: Silvana Raić-Malić (mentor)
• Committee member: Silvana Raić-Malić (predsjednik povjerenstva)
• Committee member: Šime Ukić (član povjerenstva)
• Committee member: Andrijana Meščić Macan (član povjerenstva)
• Granter: University of Zagreb; Faculty of Chemical Engineering and Technology; Zagreb
• Defense date and country: 2019-07-02, Croatia
• Scientific / art field, discipline and subdiscipline: NATURAL SCIENCES; Chemistry

Abstract

Cilj ovog rada bio je sintetizirati spojeve bazirane na konjugatima ferocena i purina i purinskih izostera povezanih 1,2,3-triazolnom premosnicom s potencijalnim citostatskim djelovanjem. Alkilirani purinski izosteri (16-21) dobiveni su reakcijom propargiliranja s propargil-bromidom u prisutstvu baze, dok su azidni derivati ferocena dobiveni iz derivata ferocena s natrijevim azidom. Pri alkiliranju 6-klorpurina i 2-amino-6-klorpurina dobivena je smjesa N-9 i N-7 regioizomera u kojoj prevladava N-9 izomer. Ciljani konjugati purina i pseudopurina i ferocena (22-37) priređeni su 1,3-dipolarnom cikloadicijom ferocenskih azida (13-15) i terminalnih purinskih i pseudopurinskih alkina (16-21) kataliziranom Cu(I) (CuAAC). Strukture spojeva potvrđene su 1H- i 13C- NMR spektroskopijom. Radi ispitivanja odnosa strukture i djelovanja (SAR), dušikovi heterocikli i ferocenski farmakofori su povezani preko 1,2,3-triazolnog prstena direktno ili preko metilenske, odnosno metilmetinske premosnice. Ispitat će se također utjecaj različito supstituiranih purina i pseudopurina na antiproliferativna djelovanja. Rezultati ispitivanja kinetičke topljivosti i lipofilnosti logD pokazali su da adeninski derivat ferocena 23 i 6-klorpurinski derivati ferocena 28 i 30-33 imaju odličnu kinetičku topljivost (> 100) i lipofilnost u rasponu od 3,09 do 4,27. Nasuprot tome, 6-klor-7-deazapurinski derivati ferocena 25, 26 i 27 su spojevi najveće lipofilnosti (logD ≥ 5,62) koji imaju i vrlo nisku topljivost. Uzimajući u obzir ispitana ispitana fizikalna svojstva, spojevi 23 i 28-35 zadovoljavaju osnovne pretpostavke topljivosti i lipofilnosti za moguću daljnju biološku primjenu.

Abstract (english)

The aim of this work was to synthesize novel purine and purine isosteres and ferrocene conjugates connected by a 1,2,3-triazolyl linker as potential new cytostatic agents. Alkylated purine isosteres (16-21) were prepared by propargylation with propargyl bromide in the presence of base, whereas the azido ferrocene derivatives were prepared from ferrocene derivatives with sodium azide. Alkylation of 6-chloropurine and 2-amino-6-chloropurine yielded a mixture of N-9 and N-7 regioisomers with the N-9 isomer as the major product. The targeted purine and pseudopurine and ferrocene conjugates (22-37) were prepared by 1,3-dipolar cycloaddition of ferrocene azides (13-15) and terminal purine and pseudopurine alkynes (16-21) catalyzed by Cu(I) (CuAAC). The structures of the synthesized compounds have been confirmed by 1H- and 13C- NMR spectroscopy. For the examination of structure-activity relationship (SAR), nitrogen heterocycles and ferrocene pharmacophores were connected via a 1,2,3-triazolyl ring directly, or with a methylene or methylmethylene linker. Antiproliferative activity of differently substituted purines and pseudopurines will also be investigated. Kinetic solubility and lipophilicity (logD) results have shown that adenine ferrocene derivative 23 and 6-chloropurine ferrocene derivatives 28 and 30-33 have great kinetic solubility (>100) and lipophilicity in the range of 3.09-4.27. On the other hand, 6-chloro-7-deazapurine ferrocene derivatives 25, 26 and 27 have the highest lipophilicity (logD≥5.62) and very low solubility. Keeping these results in mind, compounds 28 and 30-35 are meeting the basic requirements for further biological application.

• Keywords: feroceni; 1 2 3-triazoli; purini; bakrom katalizirana 1 3-dipolarna cikloadicija
• Keywords (english): ferrocenes; 1 2 3-triazoles; purines; copper(I) catalyzed 1 3-dipolar cycloaddition
• Language: croatian
• URN:NBN: urn:nbn:hr:149:289043
• Project: Number: IP-2018-01-4682; Title: Novi spojevi temeljeni na bioizosterima purina za ispitivanje njihovih antitumorskih i antipatogenih djelovanja; Acronym: PurBioCaPa; Leader: Silvana Raić-Malić; Jurisdiction: Croatia; Funder: HRZZ; Funding stream: IP
• Study programme: Title: Chemical Engineering - Graduate study; Study programme type: university; Study level: graduate; Academic / professional title: magistar/magistra inženjer/inženjerka kemijskog inženjerstva (magistar/magistra inženjer/inženjerka kemijskog inženjerstva)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access
• Created on: 2022-02-27 16:05:10