SAHAquines, Novel Hybrids Based on SAHA and Primaquine Motifs, as Potential Cytostatic and Antiplasmodial Agents. Issue 8 (21st August 2018)

• Record Type: Journal Article
• Authors: Beus, Maja; Rajić, Zrinka; Maysinger, Dusica; Mlinarić, Zvonimir; Antunović, Maja; Marijanović, Inga; Fontinha, Diana; Prudêncio, Miguel; Held, Jana; Olgen, Sureyya; Zorc, Branka
• Is Part Of: ChemistryOpen. Volume 7:Issue 8(2018)
• Page Start: 624
• Page End: 638
• Publication Date: 2018-08-21
• Subjects: acetylation -- anticancer agents -- antiplasmodial activity -- cytostatic activity -- drug design; Chemistry -- Periodicals; 540; 540.5
• DOI: 10.1002/open.201800117
• Languages: English
• ISSNs: 2191-1363

Abstract

Abstract: We report the synthesis of SAHAquines and related primaquine (PQ) derivatives. SAHAquines are novel hybrid compounds that combine moieties of suberoylanilide hydroxamic acid (SAHA), an anticancer agent with weak antiplasmodial activity, and PQ, an antimalarial drug with low antiproliferative activity. The preparation of SAHAquines is simple, cheap, and high yielding. It includes the following steps: coupling reaction between primaquine and a dicarboxylic acid monoester, hydrolysis, a new coupling reaction with O ‐protected hydroxylamine, and deprotection. SAHAquines5 a –d showed significant reduction in cell viability. Among the three human cancer cell lines (U2OS, HepG2, and MCF‐7), the most responsive were the MCF‐7 cells. The antibodies against acetylated histone H3K9/H3K14 in MCF‐7 cells revealed a significant enhancement following treatment with N ‐hydroxy‐ N ′‐{4‐[(6‐methoxyquinolin‐8‐yl)amino]pentyl}pentanediamide (5 b ). Ethyl (2 E )‐3‐({4‐[(6‐methoxyquinolin‐8‐yl)amino]pentyl}carbamoyl)prop‐2‐enoate (2 b ) and SAHAquines were the most active compounds against both the hepatic and erythrocytic stages of Plasmodium parasites, some of them at sub‐micromolar concentrations. The results of our research suggest that SAHAquines are promising leads for new anticancer and antimalarial agents. Abstract : Battling cancer : SAHAquines5 based on suberoylanilide hydroxamic acid (SAHA) and primaquine (PQ) motifs and PQ derivatives that differ in the type/length of the spacer and/or functional groups (esters2, carboxylic acids3, and O‐protected hydroxamic acids4 and6 ) are designed and synthesized. SAHAquines5 are the most active cytostatic and antiplasmodial agents. Most of these compounds exert high activity against breast adenocarcinoma (MCF‐7).