Synthesis of bis-β,β′-spiro-pyrrolidinyl-oxindoles, containing a rhodanine fragment

Evaluation of Rhodanine Indolinones as AANAT Inhibitors

“…In DMF, a peak in the LC–MS consistent with an isomer of the desired product was evident (not isolated). We settled on the conditions described by Shvets [38] involved stirring with slightly more than 1 equivalent of potassium hydroxide in methanol (Table 2: D), and it was performed at room temperature overnight. Using these conditions, the desired product was 80 % of the crude mixture by LC–MS with fewer minor product peaks, and it had an isolated yield of 44 % after recrystallization.…”

“…(Z)‐6‐(5‐(1‐(4‐Fluorobenzyl)‐2‐oxoindolin‐3‐ylidene)‐4‐oxo‐2‐thioxothiazolidin‐3‐yl)hexanoic acid (17, “rhodanine indolinone”) : We applied a method similar to that described by Shvets [38] . Stirred 1‐(4‐fluorobenzyl)indoline‐2,3‐dione 16 (50 mg, 1 equiv, 0.20 mmol) and 6‐(4‐oxo‐2‐thioxothiazolidin‐3‐yl)hexanoic acid 5 (48 mg, 1 equiv, 0.20 mmol) with methanol (1 mL) in a round bottomed flask.…”

“…The trans relationship of the rhodanine and indolinone carbonyl groups has been unambiguously established by an Xray crystal structure of a 1,3-dipolar cycloaddition adduct derived from reaction of the carbon-carbon double bond connecting the two rings [38] and also by structures of ligands containing these ring systems bound to proteins. [41][42] Also, it should be noted that most of the compounds of Tables 2 were only sparingly soluble in common organic solvents such as DCM, EtOAc, or MeOH, making chromatography quite challenging.…”

“…Rhodanines have been implicated as promiscuous binders that can be pan-assay interference compounds, [47] so initially we were concerned that changing the rhodanine ring for another heterocycle might result in loss of activity. However, we were delighted to find that other heterocycles (37)(38)(39) were tolerated, and a hydantoin ring (38) showed comparable potency to that of the rhodanine ring, itself (31 vs. 27 μM). As with 17, removal of the carboxylic acid-alkyl chain from 37-39 to give 21-23 resulted in loss of activity, suggesting that these non-rhodanines likely bind in a similar manner as 17.…”

“…[62] We applied a method similar to that described by Shvets. [38] Stirred 1-(4-fluorobenzyl)indoline-2,3-dione 16 (50 mg, 1 equiv, 0.20 mmol) and 6-(4-oxo-2-thioxothiazolidin-3-yl)hexanoic acid 5 (48 mg, 1 equiv, 0.20 mmol) with methanol (1 mL) in a round bottomed flask. Cooled the flask in an ice bath for 5 min before adding aqueous KOH (40 % w/w, 589 μL, 1.05 equiv, 0.21 mmol).…”