Synthesis and Evaluation of 1,5-Disubstituted Tetrazoles as Rigid Analogues of Combretastatin A-4 with Potent Antiproliferative and Antitumor Activity

Abstract

Tubulin, the major structural component of microtubules, is a target for the development of anticancer agents. Two series of 1,5-diaryl substituted 1,2,3,4-tetrazoles were concisely synthesized, using a palladium-catalyzed cross-coupling reaction, and identified as potent antiproliferative agents and novel tubulin polymerization inhibitors that act at the colchicine site. SAR analysis indicated that compounds with a 4-ethoxyphenyl group at the N-1 or C-5 position of the 1,2,3,4-tetrazole ring exhibited maximal activity. Several of these compounds also had potent activity in inhibiting the growth of multidrug resistant cells overexpressing P-glycoprotein. Active compounds induced apoptosis through the mitochondrial pathway with activation of caspase-9 and caspase-3. Furthermore, compound 4l significantly reduced in vivo the growth of the HT-29 xenograft in a nude mouse model, suggesting that 4l is a promising new antimitotic agent with clinical potential.

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].…”

Combretastatins: More Than Just Vascular Targeting Agents?

“…P-gp is the most characterized member of the ABC family. It is well established from numerous sources that the combretastatins are not substrates for the P-gp and thus offer a therapeutic advantage over other clinically used MTAs such as the taxanes and the vinca alkaloids, which are known P-gp substrates (Shirai et al, 1998;Gwaltney et al, 2001;Xu et al, 2008;Greene et al, 2010;Lee et al, 2010;Romagnoli et al, 2012;Penthala et al, 2013). Similarly, the combretastatins demonstrated potent activity in cancer cells overexpressing BCRP .…”

<strong>Synthesis of <em>bis</em>-heterocycles type spacer containing 1,5-disubstituted-1<em>H</em>-tetrazoles</strong>

“…Considerable attention has been focused on 1,5-disubstituted-1H-tetrazoles (1,5-DS-T) [8][9], in the field of medicinal chemistry due to their ability to mimic as cis amide bond [10][11][12]. Moreover, they are known for their pharmacophoric features, and the ability to improve pharmacokinetic and pharmacodynamic properties, increase of metabolic resistance, and decrease of toxicity or side effects [13][14][15][16][17].…”

“…Moreover, they are known for their pharmacophoric features, and the ability to improve pharmacokinetic and pharmacodynamic properties, increase of metabolic resistance, and decrease of toxicity or side effects [13][14][15][16][17]. Particularly 1,5-DS-T have been reported as privileged scaffolds in the development of antihypertensive [13], antimicrobial [13], anticonvulsant [14] and anticancer molecules [15][16][17]. Due to above mentioned medicinal importance of bis-heterocycle and 1,5-DS-T moieties individually, there has been an increased interest in the synthesis of bis-heterocycles containing 1,5-DS-T moiety over past decade.…”