Biological Effects of Modifications of the Englerin A Glycolate

Abstract

Modifications at the glycolate moiety of englerin A were made to explore variations at the most sensitive site on the molecule for activity in the NCI 60 screen, wherein englerin A is highly potent and selective for renal cancer cells. Replacement of the glycolate by other functionalities as well as esterification of the glycolate hydroxyl yielded compounds which displayed excellent selectivity and potency compared with the natural product. TRPC4/5 ion channel experiments with five compounds showed delayed or reduced agonism with TRPC5, at much higher concentrations than englerin A. With TRPC4, these compounds all had no effect at 10 μM. The same compounds were not detectable in mouse serum after a single oral dose of 12.5 mg/kg. At 100 mg/kg p.o., no toxicity was observed, and blood levels were barely detectable. Intravenous administration led to toxicity but at substantially lower doses than for englerin A.

General anaesthesia-related complications of gut motility with a focus on cholinergic mechanisms, TRP channels and visceral pain

“…We thus concluded that TRPC4 agonists may be used for the correction of GI motility suppression induced by general anesthesia. It is worth noting that there has recently been significant progress in developing nontoxic analogue of EA ( Seenadera et al, 2022 ).…”

Discovery of Triazolyl Derivatives of Cucurbitacin B Targeting IGF2BP1 against Non-Small Cell Lung Cancer

“…18,19 For instance, cinnamic acid was presented in many active molecules with good efficacy, such as (−)-Englerin A (12), which has been under intensive preclinical investigation at the NCI. 20 Orelabrutinib (13) and zytiga (14) containing a pyridine moiety have been approved for listing by the FDA. 21,22 In addition, the triazolyl group has been successfully applied in the development of selinexor (15), letrozole (16), and talzenna (17).…”

“…Cinnamic acid, , pyridine/furan , and triazolyl moieties have been considered common structures in the design of anticancer drugs due to their dipolar interaction, hydrogen bond formation ability, rigidity, and solubility. , For instance, cinnamic acid was presented in many active molecules with good efficacy, such as (−)-Englerin A ( 12 ), which has been under intensive preclinical investigation at the NCI . Orelabrutinib ( 13 ) and zytiga ( 14 ) containing a pyridine moiety have been approved for listing by the FDA. , In addition, the triazolyl group has been successfully applied in the development of selinexor ( 15 ), letrozole ( 16 ), and talzenna ( 17 ). , Furan and thiophene were used to develop tykerb ( 18 ) and orgovyx ( 19 ). , These drugs can be used effectively in cancer treatment (Figure ).…”