Design, Synthesis, and Biological Evaluation of Novel Selenium-Containing Isocombretastatins and Phenstatins as Antitumor Agents

Abstract

Two series of structurally related organoselenium compounds designed by fusing the anticancer agent methyl(phenyl)selane into the tubulin polymerization inhibitors isocombretastatins or phenstatins were synthesized and evaluated for antiproliferative activity. Most of these selenium containing hybrids exhibited potent cytotoxicity against a panel of cancel cell lines, with IC values in the submicromolar concentration range. Among them, 11a, the 3-methylseleno derivative of isocombretastatin A-4 (isoCA-4) represented the most active compound with IC values of 2-34 nM against 12 cancer cell lines, including two drug-resistant cell lines. Importantly, its phosphate salt, 11ab, inhibited tumor growth in xenograft mice models with inhibitory rate of 72.9% without apparent toxicity, which was better than the reference compounds isoCA-4P (inhibitory rate 52.2%) and CA-4P (inhibitory rate 47.6%). Mechanistic studies revealed that 11a is a potent tubulin polymerization inhibitor, which could arrest cell cycle at G/M phase and induce apoptosis along with the decrease of mitochondrial membrane potential. In summary, 11a could serve as a promising lead for the development of highly efficient anticancer agents.

Synthesis of Monofluoromethyl Selenoethers of Aryl and Alkyl from Organoselenocyanate via One‐Pot Reaction

“…To gain more insights, some control experiments were conducted (Scheme ). Treatment of selenocyanatobenzene with KOH could afford PhSeSePh in 92% yield (Scheme , a ) . To confirm that KOH indeed promoted the monofluoromethylation, we performed a reaction with PhSeSePh and ICFH 2 in the absence of KOH.…”

Synthesis of Various Derivatives of [1,3]Selenazolo[4,5‐d]pyrimidine and Exploitation of These Heterocyclic Systems as Antibacterial, Antifungal, and Anticancer Agents

“…With respect to medicine, practical application of some of the selenium-containing compounds for the treatment of tumors and cancers is a subject of current intense interest. [9,15,[41][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56] Moreover, in terms of material science, five-membered organoselenium heterocycles have been utilized in developing organic conductors, semiconductors, optoelectronics, and fluorescent probes. [57][58][59][60][61][62] Amongst heterocyclic organoselenium cores, the 1,3-selenazole skeleton has received much attention in many pharmacologically active substances like selenazofurin (I) and amselamine (II).…”

An Efficient Selectfluor-Mediated Oxidative Thio- and Selenocyanation of Diversely Substituted Indoles and Carbazoles

“…Aryl thio-and selenocyanates are versatile intermediates for various sulfur-and selenium-containing compounds that are of synthetic and biological interest [14][15][16][17][18][19][20][21][22][23][24][25][26]. Aryl thiocyanates are widely employed as building blocks in the synthesis of diverse sulfides [27,28], thiocarbamates [29], thionitriles [30], sulfonic acids [31], sulfonyl chlorides [32], thioesters [33], and sulfonyl cyanides [31] and mainly in the synthesis and functionalization of heterocyclic compounds [25,26,[34][35][36][37][38][39][40].…”

“…In particular, direct oxidative thiocyanation of C-H bonds have been achieved by using thiocyanate salts in the presence of oxidizing agents such as Mn(OAc) 3 [15], NCS [47], CAN [48], hypervalent iodine reagents [49], DDQ [50], oxone [51], oxygen [52], DEAD [53], and TBHP [22]. In comparison, direct selenocyanation approaches have not been reported under similar oxidative conditions [20][21][22][23][24][25][26]. Therefore, developing new and broad-based protocols for direct introduction of SCN and SeCN moieties into organic structures, in particular those motifs that are important for medicinal chemistry as building blocks of pharmaceuticals, continues to be relevant.…”