Regioselective Suzuki Coupling of Dihaloheteroaromatic Compounds as a Rapid Strategy To Synthesize Potent Rigid Combretastatin Analogues

Abstract

Combretastatin A-4 (CA-4) is a potent tubulin depolymerizing agent able to inhibit tumor growth and with antivascular effects. Although it is in clinical trials, the search for novel analogues that may display better/different features is still ongoing. In this manuscript we describe the synthesis of novel constrained analogues of CA-4 obtained in only two synthetic steps exploiting a regioselective Suzuki coupling of dihalogenated heteroaromatic and alicyclic compounds. All the compounds synthesized have been evaluated for cytotoxicity and for their ability to inhibit tubulin assembly. One of them, 38, displayed low nanomolar cytotoxicity and proved to have a pharmacodynamic profile similar to that of CA-4 and a better pharmacokinetic profile, but most important of all, this synthetic strategy may pave the way for the easy and rapid generation of novel rigid analogues of combretastatins.

Tubulin-interactive stilbene derivatives as anticancer agents

“…The rationale of the design of active compounds was to retain the appropriate geometry of the two adjacent aryl groups required for potent bioactivity of chemically stable cis-restricted derivatives of CA-4. These were obtained by incorporating the olefinic double bond into vicinally diaryl-substituted fivemember aromatic heterocyclic rings (Table 1), such as pyrazole [67], imidazole [67][68][69], thiazole [70][71][72], furazan (1,2,5-oxadiazole) [73], furan [74,75], thiophene [76,77], isoxazole [78,79], oxazole [67,68,80,81], 1,2,3-thiadiazole [39], triazole [82,83,84,85], 1,2,3,4-tetrazole [70,86] and dioxolane [87]. Replacement of the olefinic bond with a five-member heterocyclic ring allowed the retention of the correct geometric orientation of the two phenyl rings of CA-4, placing them at an appropriate distance for efficient interaction with the colchicine-binding domain on tubulin [35].…”

Palladium (0) catalyzed Suzuki cross-coupling reactions of 2,4-dibromothiophene: selectivity, characterization and biological applications

“…[1,2] One such important class of compounds is biaryl thiophenes, which have been successfully used as chemotherapeutic, [3] anti-inflammatory, [4] antibacterial, [5] antifungal, [6] antiviral, [7] antioxidant, [8] insecticidal, [9] anti-nociceptive, [10] anti-tubercular, [11] anti-diabetic [12] and anti-depressant agents, [13] Earlier, the regioselective couplings of dibromothiophenes have been studied in detail, [14,15] Schroter and co-workers revealed in their work that the coupling of 2,4-dibromothiophene can be successfully achieved by following the Suzuki cross-coupling reaction, whereas Kumda or Sonogashira found that the couplings preferably occurs at C-2 position in thiophenes. [2] Varello and co-workers reported the one-pot couplings of 2,4-dibromothiophene through the Suzuki-Miyaura coupling reaction.…”

Synthesis and biological activity of pyrrole analogues of combretastatin A-4

“…[1][2][3][4][5][6][7][8][9][10][11][12][13] Combretastatin A-4 binds to the colchicine (1) domain of tubulin and inhibits microtubule polymerisation, resulting in destabilisation of the microtubule cytoskeleton and inhibition of mitosis. The structural simplicity and potent cytotoxicity of CA-4 has led to the development of analogues of CA-4 as new anticancer agents (Fig.…”

“…The 3,4,5-trimethoxy group on ring A affects cytotoxic activity and 3-hydroxy-4-methoxy groups on ring B affects binding to tubulin. 1,4,5,8,13 In terms of the spatial relationship, the cis-orientation of the two rings of CA-4 is required for binding in the colchicine-binding site of tubulin. Nevertheless, it is notable that the cis-olefin in CA-4 can convert into the thermodynamically more stable, and inactive, trans-olefin due to its metabolic instability.…”

“…1,2,5,7,9,14 The low water-solubility of CA-4 results in its low efficacy in vivo and therefore the water-soluble sodium phosphate prodrug of CA-4, fosbretabulin (CA-4P), was designed and is currently in phase II/III clinical trials. [5][6][7][8][9][10][11] Efforts to remove the possibility of cis-trans isomerisation have been attempted by replacing the cis-olefin with a five-membered heterocycle which result in a cis-like constrained configuration. CA-4 analogues having five-membered heterocyclic rings such as oxazoles, imidazoles and triazoles have been reported to have increased potency and bioactivity.…”