Green Synthesis of 3,4'-Pyrano[2,3-c]pyrazole-spirooxindole Derivatives and Their Antiproliferation Activities against Lung Cancer

doi:10.6023/cjoc202603039

Abstract

In an effort to discover novel compounds active against drug-resistant lung cancer, 21 3,4'-pyrano[2,3-c]pyrazole-spirooxindole derivatives were synthesized via an environmentally friendly procedure using 5-phenyl-2,4-dihydro-3H-pyrazol-3-one, malononitrile, and isatin as starting materials. In vitro anti-lung cancer activity evaluation revealed that these compounds exhibited potent inhibitory activity not only against parental A549 cells but also against cisplatin-resistant A549/DDP cells. In particular, 6'-amino-7-chloro-2-oxo-3'-phenyl-2'H-spiro[indoline-3,4'-pyrano[2,3-c]pyrazole]-5'-carboni-trile (HDY-3) exhibited exceptional potency against the A549/DDP cells, with activity 92-fold higher than that of the positive control drug cisplatin. Mechanistic studies indicated that HDY-3 significantly blocked the cell cycle of A549/DDP cells at both the G₀/G₁ and G₂/M phases, induced apoptosis, and suppressed cell migration. Furthermore, molecular docking, molecular dynamics simulations, and MM/GBSA binding free energy calculations revealed that the HDY-3-ERK1 complex exhibited high stability and strong binding affinity. The antitumor activity of HDY-3 is likely mediated through inhibition of ERK1, thereby interfering with the RAS-RAF-MEK1/2-ERK1/2 signaling pathway. Collectively, these results suggest that compound HDY-3 can serve as a lead compound for further development into highly effective anti-lung cancer drugs.

Key words: 3-spirooxindole, green synthesis, derivative, antitumor activity

Cite this article

Jun Yang, Dongyan Huang, Guangping Liang, Xiongwei Liu. Green Synthesis of 3,4'-Pyrano[2,3-c]pyrazole-spirooxindole Derivatives and Their Antiproliferation Activities against Lung Cancer[J]. Chinese Journal of Organic Chemistry, 2026, 46(10): 3970-3982.

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Compd.	R¹	R²	R³	R⁴	R⁵	Yield/%
HDY-1	H	Cl	H	H	H	96
HDY-2	H	OCH₃	H	H	H	98
HDY-3	H	H	H	Cl	H	77
HDY-4	H	H	H	CH₃	H	82
HDY-5	H	Br	H	H	H	90
HDY-6	H	H	Cl	H	H	92
HDY-7	H	H	H	Br	H	76
HDY-8	Br	H	H	H	H	79
HDY-9	H	H	F	H	H	97
HDY-10	H	F	F	H	H	90
HDY-11	H	NO₂	H	H	H	93
HDY-12	H	H	H	NO₂	H	86
HDY-13	H	H	OCH₃	H	H	93
HDY-14	H	H	H	H	CH₃	77
HDY-15	H	F	H	H	H	87
HDY-16	Cl	H	Cl	H	H	90
HDY-17	H	Br	H	H	CH₃	82
HDY-18	H	H	H	F	CH₃	89
HDY-19	H	H	H	H	Ph	77
HDY-20	H	H	H	H	H	96
HDY-21	H	CH₃	H	H	H	91

Compd.	R¹	R²	R³	R⁴	R⁵	Yield/%
HDY-1	H	Cl	H	H	H	96
HDY-2	H	OCH₃	H	H	H	98
HDY-3	H	H	H	Cl	H	77
HDY-4	H	H	H	CH₃	H	82
HDY-5	H	Br	H	H	H	90
HDY-6	H	H	Cl	H	H	92
HDY-7	H	H	H	Br	H	76
HDY-8	Br	H	H	H	H	79
HDY-9	H	H	F	H	H	97
HDY-10	H	F	F	H	H	90
HDY-11	H	NO₂	H	H	H	93
HDY-12	H	H	H	NO₂	H	86
HDY-13	H	H	OCH₃	H	H	93
HDY-14	H	H	H	H	CH₃	77
HDY-15	H	F	H	H	H	87
HDY-16	Cl	H	Cl	H	H	90
HDY-17	H	Br	H	H	CH₃	82
HDY-18	H	H	H	F	CH₃	89
HDY-19	H	H	H	H	Ph	77
HDY-20	H	H	H	H	H	96
HDY-21	H	CH₃	H	H	H	91

Compd.	IC₅₀^a/(μmol•L^-1)
Compd.	A549	A549/DDP	RF^b
HDY-1	0.044±0.001	0.711±0.018	16.03
HDY-2	0.297±0.006	0.453±0.006	1.53
HDY-3	0.115±0.002	0.027±0.001	0.23
HDY-4	0.111±0.004	0.885±0.030	7.97
HDY-5	1.201±0.021	0.024±0.001	0.02
HDY-6	0.105±0.003	0.073±0.003	0.70
HDY-7	1.502±0.007	0.471±0.007	0.31
HDY-8	2.899±0.086	0.228±0.004	0.08
HDY-9	0.089±0.003	0.420±0.002	4.72
HDY-10	0.463±0.010	0.759±0.015	1.64
HDY-11	0.422±0.017	0.030±0.001	0.07
HDY-12	3.851±0.156	0.800±0.007	0.21
HDY-13	0.013±0.001	0.085±0.004	6.79
HDY-14	0.259±0.011	0.238±0.003	0.92
HDY-15	0.181±0.004	0.332±0.008	1.83
HDY-16	0.205±0.005	0.418±0.007	2.04
HDY-17	0.107±0.003	1.321±0.027	12.37
HDY-18	0.189±0.006	0.411±0.008	2.18
HDY-19	0.255±0.005	3.477±0.038	13.66
HDY-20	0.112±0.002	0.304±0.004	2.71
HDY-21	0.037±0.001	0.065±0.001	1.73
Cisplatin	1.480±0.008	2.496±0.117	1.69

Compd.	IC₅₀^a/(μmol•L^-1)
Compd.	A549	A549/DDP	RF^b
HDY-1	0.044±0.001	0.711±0.018	16.03
HDY-2	0.297±0.006	0.453±0.006	1.53
HDY-3	0.115±0.002	0.027±0.001	0.23
HDY-4	0.111±0.004	0.885±0.030	7.97
HDY-5	1.201±0.021	0.024±0.001	0.02
HDY-6	0.105±0.003	0.073±0.003	0.70
HDY-7	1.502±0.007	0.471±0.007	0.31
HDY-8	2.899±0.086	0.228±0.004	0.08
HDY-9	0.089±0.003	0.420±0.002	4.72
HDY-10	0.463±0.010	0.759±0.015	1.64
HDY-11	0.422±0.017	0.030±0.001	0.07
HDY-12	3.851±0.156	0.800±0.007	0.21
HDY-13	0.013±0.001	0.085±0.004	6.79
HDY-14	0.259±0.011	0.238±0.003	0.92
HDY-15	0.181±0.004	0.332±0.008	1.83
HDY-16	0.205±0.005	0.418±0.007	2.04
HDY-17	0.107±0.003	1.321±0.027	12.37
HDY-18	0.189±0.006	0.411±0.008	2.18
HDY-19	0.255±0.005	3.477±0.038	13.66
HDY-20	0.112±0.002	0.304±0.004	2.71
HDY-21	0.037±0.001	0.065±0.001	1.73
Cisplatin	1.480±0.008	2.496±0.117	1.69

Compd.	IC₅₀^a/(μmol•L^-1)
Compd.	A549	A549/DDP	BEAS-2B	SI^b	SI^c
HDY-3	0.115±0.002	0.027±0.001	8.726±0.518	75.88	323.18
Cisplatin	1.480±0.008	2.496±0.117	2.539±0.244	1.71	1.02

3,4'-吡喃并[2,3-c]吡唑螺吲哚酮衍生物的绿色合成及抗肺癌活性研究