A series of isatin−dihydropyrazole hybrids have been synthesized in order to assess their potential as anticancer agents. In particular, 12 compounds were evaluated for their antiproliferative activity toward A549, IGR39, U87, MDA-MB-231, MCF-7, BT474, BxPC-3, SKOV-3, and H1299 cell lines, and human foreskin fibroblasts. Four compounds exhibited interesting antiproliferative activity and were further examined to determine their EC 50 values toward a panel of selected tumor cell lines. The best compounds were then investigated for their induced mechanism of cell death. Preliminary structure−activity relationship indicates that the presence of a substituent such as a chlorine atom or a methyl moiety in position 5 of the isatin nucleus is beneficial for the antitumor activity. EMAC4001 proved the most promising compound within the studied series with EC 50 values ranging from 0.01 to 0.38 μM.
The asymmetric synthesis
of novel 3-substituted isoindolinones
is herein reported. A new cascade reaction was developed that consisted
of the asymmetric nitro-Mannich reaction of suitable α-amido
sulfones designed from 2-formyl benzoates, followed by the
in situ
cyclization of the adducts. Very high enantioselectivities,
up to 98% ee, and very good yields were obtained in the presence of
the readily available neutral bifunctional organocatalyst derived
from
trans
-1,2-diaminocyclohexane, which is known
as Takemoto’s catalyst. The investigation of the reactivity
of the obtained products allowed either the selective Boc-deprotection
or reduction of the nitro group, leading to further functionalized
3-substituted isoindolinones without affecting the enantiomeric purity.
A highly stereoselective access to 3-sulfinyl-substituted isoindolinones has been achieved by a tandem organocatalytic addition/cyclization reaction of 2-carbobenzyloxy-N-tosylbenzylidenimine with thiols and succeeding diastereoselective oxidation with MCPBA. First, enantioenriched isoindolinone N,S-acetals have been obtained through a dynamic kinetic asymmetric transformation induced by a bifunctional chiral thiourea organocatalyst. In turn, the newly created carbon stereocenter enabled a high diastereocontrol in the subsequent sulfoxidation. Based on DFT calculations, a theoretical rationale for the stereoselectivity of the oxidation reaction is also provided.
An original tandem reaction consisting of a Wittig reaction−ring contraction process between α-hydroxycyclobutanone and phosphonium ylides has been developed. Highly functionalized cyclopropanecarbaldehydes are obtained in good to high yield.
We herein report a protocol for the asymmetric aldol‐initiated cascade addition of isoxazolidin‐5‐ones to ortho‐cyanobenzaldehydes by using Takemoto’s bifunctional organocatalyst. This approach allows for the synthesis of various novel β2,2‐amino acid‐phthalide conjugates with good enantio‐ and diastereoselectivities in reasonable yields and the further ring‐opening of these compounds to acyclic carboxylic acid derivatives was demonstrated too.
Herein, we report the application of an efficient and practical K2CO3 promoted cascade reaction of 2-acetylbenzonitrile in the synthesis of novel 3-methylated analogs of Pazinaclone and PD172938, belonging to isoindolinones heterocyclic class bearing a tetrasubstituted stereocenter. Organocatalytic asymmetric synthesis of the key intermediate and its transformation into highly enantioenriched 3-methylated analog of (S)-PD172938 was also developed. These achievements can be of particular interest also for medicinal chemistry, since the methyl group is a very useful structural modification in the rational design of new and more effective bioactive compounds.
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