Bis(pentafluorosulfanyl)phenyl Azide as an Expeditious Tool for Click Chemistry toward Antitumor Pharmaceuticals

Abstract

The inclusion of fluorine in pharmaceutical agents is a well- established means of improving their druglike properties. Different substituents have been used to introduce fluorine, including trifluoromethyl and trifluoromethylthio groups; however, the pentafluorosulfanyl remains relatively underutilized although it is considered to be a "super" trifluoromethyl group. Here, a series of pentafluorosulfanyl-containing 1,4-disubstituted-1,2,3-triazoles were synthesized by click reaction from alkynes and 3,5-bis(pentafluorosulfanyl)phenyl azide in excellent yields. Their biological activities were evaluated against human leukemic monocyte lymphoma U937 cells. In particular, 1-(3,5-bis(pentafluorosulfanyl)phenyl)-4-(4-fluorophenyl)-1H-1,2,3-triazole exhibited potent efficacy in cell viability assays at a concentration of 60 μM and was shown to activate caspase-3 activity, indicating induction of apoptosis. An analogous fluorenol-substituted triazole also exhibited promising cytotoxic effects against U937 cells, with an IC50 value of 6.29 μM. Given these preliminary results, these pentafluorosulfanyl-containing triazoles represent useful building blocks for the further development of novel antitumor agents.

Synthesis of fluoro-functionalized diaryl-λ3-iodonium salts and their cytotoxicity against human lymphoma U937 cells

“…2 ), 3m has a lower IC 50 value of 0.68 μM than that of 3k (2.45 μM), as evaluated by the MTT assay. The best potency and IC 50 value (0.49 μM) was obtained for SF 5 type 3p , which is quite impressive when compared to the well-known antitumor drug cytosine arabinoside (ara-C), (0.16 μM) [ 27 ].…”

“…The U937 cell line is maintained as replicative non-adherent cells having many of the biochemical and morphological characteristics of blood monocytes. This cell line was chosen due to the convenience with which it can be handled and its ease of growth [ 27 ]. Initially, 19 compounds [ 20 – 22 59 – 64 ] were examined for their potential cytotoxicity, and some of them showed potency, in particular ortho -fluoro-functionalized diaryliodonium salts.…”

Preparation of (Pentafluorosulfanyl)benzenes by Direct Fluorination of Diaryldisulfides: Synthetic Approach and Mechanistic Aspects

“…Given that SF 3 is a strong electron‐acceptor group, once the bis‐SF 3 aromatic was formed, further fluorination took place. Aryl bromide 3 w has been widely used for the introduction of a 3,5‐bis(pentafluorosulfanyl)phenyl moiety in the synthesis of Pd complexes, in medicinal chemistry, in dye synthesis, and in catalyst design …”

“…We presumet hat the formation of cyclic (or linear in the case of 2d)o ligomeric aromatic disulfides took place initially,f ollowedb yf luorination with F 2 .G iven that SF 3 is as trong electron-acceptor group, once the bis-SF 3 aromatic was formed, further fluorination took place. Aryl bromide 3w has been widely used for the introduction of a3 ,5-bis(pentafluorosulfanyl)phenyl moietyi nt he synthesis of Pd complexes, [27] in medicinal chemistry, [28] in dye synthesis, [29] and in catalystdesign. [30] Translating the fluorination from batch setup to af low process mightl ead to increased yields and better selectivity.…”

Studies of Halogen Bonding Induced by Pentafluorosulfanyl Aryl Iodides: A Potential Group of Halogen Bond Donors in a Rational Drug Design

“…[36][37][38][39][40][41] More and more examples of biologically active SF5-contaning drug candidates have been reported in recent years ( Figure 1c). [34,[37][38][39][40][41] Extending our research to the design and synthesis of SF5-containing biologically attractive molecules [42][43][44][45][46][47][48][49][50][51][52][53][54] and a halogen bonding research program, [55,56] we are interested in aryl iodides 1a-d consisting of SF5-group(s) in the benzene ring as potential drug fragments capable of halogen bonding, in particular, 3,5-bis-pentafluorosulfanyl iodobenzene 1d (Figure 1d).…”