A Facile Synthesis of Novel Isatinspirooxazine Derivatives and Potential in vitro Anti-Proliferative Activity

Abstract

Novel isatinspirooxazine derivatives were designed and synthesized as potential anti-proliferative agents. The new compounds were obtained from aldol condensation reactions between isatin and 3-(hydroxyimino)butan-2-one in the presence of an organic base in order to generate an aldol adduct, followed by cyclization in trifluoroacetic acid, providing the desired isatinspirooxazines in 30 to 80% yield. All the synthesized compounds, including the starting material and the synthetic intermediates, were tested for in vitro anti-proliferative activity against cell lines MCF-7 and MDA-MB231 (breast cancer) and A549 (lung cancer), highlighting the compound 4-methyl,5'-methyl-spiro[(5-aza-4-eno-3-one-cyclohexane)-1,3'-(1H-indol-one)] with an IC 50 (half maximal inhibitory concentration) = 0.34 μM, more potent than the reference drug, doxorubicin (IC 50 = 1.88 μM), in breast cancer line MDA-MB231.

6′-Amino-5,7-dibromo-2-oxo-3′-(trifluoromethyl)-1′H-spiro[indoline-3,4′-pyrano[2,3-c]pyrazole]-5′-carbonitrile

“…The solvents and reagents were purchased from commercial sources and used as received. 5,7-Dibromoisatin 1 was obtained from isatin according to the literature [22]. 5-(Trifluoromethyl)-2,4-dihydro-3H-pyrazol-3-one 3 was synthesized according to the standard procedure [23].…”

Novel Greener Microwave-Assisted Deprotection Methodology for the 1,3-Dioxolane Ketal of Isatin Using Calix[n]arenes

“…22 Many analogues of isatin have been prepared to find new bioactive compounds, particularly those with antiviral, anti-inflammatory, anticonvulsant, antichagasic, and antitumor activity. 21,[23][24][25][26] This is the case for the antitumor compound sunitinib (2), 27 the analgesic pemedolac (3), 28 isatins bearing halogens and nitro groups in the aromatic ring (4, 5, and 6), 29,30 and isatin-type 5'-(4-alkyl/aryl-1H-1,2,3-triazoles) (7 and 8). 31,32 In nature, isatin derivatives can be found in the parotid gland of Bufo, bacteria (Streptomyces albus), fungi (Chaetomium globosum), and other organisms such as mammals and plants.…”