Design, synthesis and in vitro anti-Zika virus evaluation of novel Sinefungin derivatives

Abstract

We report herein the design and synthesis of a series of novel Sinefungin (SIN) derivatives, based on the structures of SIN and its analogue EPZ004777. Our results reveal that target compounds 1ad-af, 1ba-bb and 1bf-bh show better activity (IC = 4.56-20.16 μM) than EPZ004777 (IC = 35.19 μM). Surprisingly, SIN was founded to be not as active (IC > 50 μM) as we and other research groups predicted. Interestingly, the intermediates 9a-b and 11b display potent anti-ZIKV potency (IC = 6.33-29.98 μM), and compound 9a also exhibits acceptable cytotoxicity (CC > 200 μM), suggesting their promising potential to be leads for further development.

The S‐adenosylmethionine analog sinefungin inhibits the trimethylguanosine synthase TGS1 to promote telomerase activity and telomere lengthening

“…In addition, sinefungin is a potent inhibitor of different parasitic protozoa [53][54][55][56][57], and a candidate therapeutic agent for treatment of CBSdeficient homocystinuria [58] and renal fibrosis [59]. These multiple therapeutic properties of sinefungin stimulated searches for its chemical analogs, so as to devise tailored treatments with optimized efficiency and tolerability [60][61][62][63][64][65][66][67][68]. Some of these compounds could now be tested on cells and animal models bearing mutations in TBD genes to identify the most suitable candidates for therapy of different short telomere diseases.…”

Drugs for the Treatment of Zika Virus Infection

“…94 This inhibitor and its analogues are of particular interest for antiviral drug development in that 16 has been shown to have broad flavivirus activity against WNV, DENV-2, and YFV. 95 Although 16 has shown activity against purified ZIKV MT in enzymatic assays, 59 it surprisingly was found to be inactive against ZIKV in a follow-up study that tested the parent compound in parallel with an analogue series. 95 The synthesis of 3-fluoro-or chlorobenzyl derivatives at the N-6 position of the adenine moiety in 16, a strategy used effectively to generate potent inhibitors of DENV-3 MT, 96 was employed to generate additional putative ZIKV MT inhibitors.…”

“…95 Although 16 has shown activity against purified ZIKV MT in enzymatic assays, 59 it surprisingly was found to be inactive against ZIKV in a follow-up study that tested the parent compound in parallel with an analogue series. 95 The synthesis of 3-fluoro-or chlorobenzyl derivatives at the N-6 position of the adenine moiety in 16, a strategy used effectively to generate potent inhibitors of DENV-3 MT, 96 was employed to generate additional putative ZIKV MT inhibitors. 95 The best compound from this optimization, 17, showed both activity (IC 50 = 29.98 μM) and acceptable toxicity (CC 50 > 200 μM).…”

“…95 The synthesis of 3-fluoro-or chlorobenzyl derivatives at the N-6 position of the adenine moiety in 16, a strategy used effectively to generate potent inhibitors of DENV-3 MT, 96 was employed to generate additional putative ZIKV MT inhibitors. 95 The best compound from this optimization, 17, showed both activity (IC 50 = 29.98 μM) and acceptable toxicity (CC 50 > 200 μM). X-ray crystallography and molecular docking were used to optimize compounds targeting ZIKV MT via a fragment-based approach.…”

Asymmetric Total Synthesis of C9′-epi-Sinefungin

“…Recently, sinefungin was shown to prevent myofibroblast activity in both cell culture and in vivo , reducing myofibroblast activity in tumor stroma and metastasis burden in lungs in a mouse cancer model . Sinefungin has also emerged as a privileged scaffold in the development of potent and selective inhibitors of SAM-dependent MTs. , Structural modification of sinefungin led to the development of a selective N -alkyl inhibitor ( 3 ) of SETD2, a tumor-suppressing protein lysine methyltransferase (PKMT) whose aberrant activity is associated with multiple developmental pathologies and cancers . The elaboration of a cyclohexyl-substituted analogue of sinefungin ( 4 ) displaying inhibitory properties toward the PKMTs EHMT1 and EHMT2 with good selectivity was also reported …”