Regioselective approach to colchiceine tropolone ring functionalization at C(9) and C(10) yielding new anticancer hybrid derivatives containing heterocyclic structural motifs

Abstract

The influence of base type, temperature, and solvent on regioselective C(9)/C(10) “ click ” modifications within the tropolone ring of colchiceine ( 2 ) is investigated. New ether derivatives of 2 , bearing alkyne, azide, vinyl, or halide aryl groups enable assembly of the alkaloid part with heterocycles or important biomolecules such as saccharides, geldanamycin or AZT into hybrid scaffolds by dipolar cycloaddition (CuAAC) or Heck reaction. Compared to colchicine ( 1 ) or colchiceine ( 2 ), ether congeners, as e.g. 3e [IC 50 s ( 3e) ∼ 0.9 nM], show improved or similar anticancer effects, whereby the bulkiness of the substituents and the substitution pattern of the tropolone proved to be essential. Biological studies reveal that expanding the ether arms by terminal basic heterocycles as quinoline or pyridine, decreases the toxicity in HDF cells at high anticancer potency (IC 50 s ∼ 1–2 nM). Docking of ether and hybrid derivatives into the colchicine pocket of α GTP /β tubulin dimers reveals a relationship between the favourable binding mode and the attractive anticancer potency.

Iron‐catalyzed intermolecular and intramolecular cyclization reactions of N‐heterocycles

“…Their innate ability as drug builders called these to be used as drug production substrates (Figure 1). Many indole and azaindole derivatives have emerged as more powerful cancer drugs [4,5]. Many quinazoline compounds have been found antiviral, anti-tubercular, and antibacterial properties [6], as well as tyrosine kinase [7] receptors, and many as EGF inhibitors [8].…”

Synthesis and antitumoral evaluation of natural product‐like compounds based on tropolone and benzotropolone derivatives

“…[12][13][14][15][16][17][18][19] Several of the compounds prepared using diazo or nitroso dienophiles in the [4+2] cycloaddition step displayed good antiparasitic and antitumoral activity, [12][13][14]18] indicating that the approach is a valuable tool for the identification of structurally novel leads with diverse biological activity. In addition, a number of recent reports describe a number of tropolone and benzotropolone derivatives with activities that rival those of cisplatin and colchicine, [20][21][22][23] further showcasing the potential of these aromatic dienes as scaffolds in the design of novel antineoplastic agents. Therefore, and taking as a starting point some of the compounds we recently obtained using alkene dienophiles, [16,19] we set out to expand our library of homobarrelenones, norcaranes, and dihydrofluorenones, and evaluate their activity against a representative panel of tumor cell lines.…”

Cascade Transformation of the Ansamycin Benzoquinone Core into Benzoxazole Influencing Anticancer Activity and Selectivity

“…In the search for new anticancer agents, GDM was modified mainly within the benzoquinone portion at C(17) and C(19). − Some of the ansamycins containing a benzene core showed enough promising anticancer activities to be considered in clinical trials . Therefore, many different approaches involving semisynthetic, mutasynthetic, and genetic manipulations have been applied to benzenoid ansamycins in order to reduce the quinone, improve useful biological potency, and decrease toxicity. ,− Modifications of the GDM core via the fusion of additional rings, imidazole, morpholine, benzo­[ g ]­quinoxaline, benzoxazine, oxazolidine, and tetrahydrodiazepine at C(17)–C(18), were rarely accompanied by reduction of the quinone core. Moreover, reported synthetic strategies did not enable further tailoring of the structure of the attached substituent to the core toward interactions with the target (heat shock protein Hsp90). , Modern synthetic strategies affording benzoxazole systems are based mainly on bifunctional reactants. − Unfortunately, these approaches allow the transformation of bifunctional reactants via intermolecular reactions utilizing metal catalysts, which is in contradiction to green chemistry rules. , To the best of our knowledge, benzoxazoles have never been obtained via an intramolecular and metal-free strategy directly from amino-benzoquinones as a starting material, whereas approaches with metal catalysts are very widespread. − …”