ACAT inhibitors derived from hetero-Diels-Alder cycloadducts of thioaldehydes

α-Substituted Malonester Amides: Tools To Define the Relationship between ACAT Inhibition and Adrenal Toxicity

“…Another study in rabbits demonstrated severe cellular damage with XP767 at doses between 10 and 100 mg/kg; however, a structurally related analogue, XR920, produced no adrenal changes, despite having similar in vitro potency to XP767. 19 Long-term incubations of potent ACAT inhibitors (SaH 58-035 and CP-113,818) with cholesterolenriched mouse peritoneal macrophages led the authors to conclude that ACAT inhibition in these cells increased cell toxicity due to the build-up of intracellular free cholesterol concentrations. This was supported by the observations that cell toxicity paralleled the increase in intracellular free cholesterol concentrations and that removal of free cholesterol by the addition of extracellular cholesterol "acceptors" or by blocking intracellular sterol transport relieved the ACAT inhibitor-induced toxicity.…”

“…These authors speculated that, because of the structural similarity between FR 145237 and PD 132301-2, the toxicity induced by FR 145237 may not be due to ACAT inhibition but to inhibition of mitochondrial respiration. Another study in rabbits demonstrated severe cellular damage with XP767 at doses between 10 and 100 mg/kg; however, a structurally related analogue, XR920, produced no adrenal changes, despite having similar in vitro potency to XP767 . Long-term incubations of potent ACAT inhibitors (SaH 58-035 and CP-113,818) with cholesterol-enriched mouse peritoneal macrophages led the authors to conclude that ACAT inhibition in these cells increased cell toxicity due to the build-up of intracellular free cholesterol concentrations.…”

Base-Promoted Reaction of 4-Chloro-3-vinyl Coumarins, Phenacylpyridinium Bromides, and Elemental Sulfur: A Designed Approach to Thiopyrano[4,3-c]chromen-5(1H)-ones

“…One of the primary goals of organic and medicinal chemistry is the design and synthesis of prominent bioactive molecules. In this regard, thiopyrans are interesting structural units, found in many therapeutic agents, and functional materials. − These compounds exhibit interesting pharmaceutical activities, including antipsoriatic, antiviral, and antiatherosclerosis activities. Furthermore, they are prominent synthetic blocks in the synthesis of some natural products .…”

Organocatalytic Enantioselective (4+2) Annulation of Cyclopropane Carbaldehydes with 2‐Mercapto‐1‐Arylethanones

“…[1] Among them, six-membered sulfur-heterocyclic moieties, i. e., dihydrothiopyrans are present in various biological compounds as well as in promising pharmaceutical drugs such as antiviral, [2] antipsoriatic, [3] antiatherosclerosis, etc. [4] In recent years, the utilization of organocatalytic methodologies has proven to be a convenient avenue for achieving an asymmetric synthesis of sulfur heterocycles. This approach has gained significant attraction among numerous research groups, who have dedicated their efforts to exploring diverse methodologies for constructing five and six-membered heterocyclic scaffolds, acknowledging the pivotal role played by these compounds.…”