Novel Furan-2(3H)-one derivatives as promising anticancer agents against liver and breast cancers cell lines: Green Synthesis, Spectroscopic analysis, in Vitro Antiproliferative Activity, and DFT study

doi:10.21203/rs.3.rs-4926797/v1

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Novel Furan-2(3H)-one derivatives as promising anticancer agents against liver and breast cancers cell lines: Green Synthesis, Spectroscopic analysis, in Vitro Antiproliferative Activity, and DFT study

https://doi.org/10.21203/rs.3.rs-4926797/v1

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Some new biologically active heterocyclic compounds were synthesized upon green reaction of (Z)-3-(benzo[d][1,3]dioxol-5-ylmethylene)-5-phenylfuran-2(3H)-one (L)with different electrophilic and nucleophile reagents under ultrasonic irradiation. The electronic structure of synthesized prepared materials was elucidated using FTIR, ¹H-NMR, ¹³C-NMR, and X-ray diffraction, elemental analysis, and melting point. The new compounds were examined for invitro ant proliferative action towards HepG-2, HCT116, MCF-7, and the normal human skin fibroblasts (BJ-1) cell lines. The results showed that: five investigated compounds could be considered as good selective ant proliferative candidate drugs for only human liver cancer as their effects on this cancer type are much more toxic compared to their toxicity on the human healthy cells. DFT Study of the new compounds showed that pyrrolone derivatives L3, L4, LN, and azapyrrolone L5 (pyrimidinone) have the maximum electron transfer for inhibition for cancer cells.

Biological sciences/Biochemistry

Biological sciences/Biological techniques

Furan-2(3H)-one

HepG-2

HCT116

MCF-7

Normal human skin fibroblast

DFT study

The cancer of the breast is one of the most common female diseases and one of the most prevalent kinds of cancer overall ^1,2. The American Cancer Society estimates that in 2020, breast cancer will be the sixth most common cause of cancer death globally ^3,4. Breast Cancer risk factors are still being discovered ^5,6. The backbone of BC therapy is principally chemotherapy avoiding severe side effects, the more specific and safer anti-BC agents are synthesized ^7,8. Varied factors, both endogenous and external, can induce breast cancer and have various effects ^9,10. Because of its aggressive characteristics, treating invasive BC can be difficult ^9,11. A large amount of research indicates that if distant metastasis can be suppressed, long-term survival may be improved ^12,13. Treatment for breast cancer relies on a mechanism or mechanisms that are already targets for pharmaceuticals that are classified as anti-tumors, whether they are synthetic or natural ones ^14,15. Depending on the existence of molecular markers, Breast cancer is classified into three types: hormonal receptor-positive/human epidermal growth factors receptors-2 gene (ERBB2) negative, triple negative, and ERBB2 positive ¹⁶. These types of cancer dictate the rate of recurrence and numerous approaches to treatment, including surgery, hormonal therapy, radiation therapy, cancer chemotherapy, or a mix of these ^17,18. Taking drugs that either competitively prevent estrogen from binding to its receptors or prevent androgens from being converted to estrogen lowers the amount of circulating estrogen. These drugs are part of standard endocrine therapy. These drugs have side effects such as osteoporosis, arthralgia, myalgia, hot flashes, and uterine cancer. Reviews of the literature did not come as a surprise when they showed that numerous heterocyclic and/or other scaffolds have been created as agents to prevent breast cancer ^19–21. 2(5H)-Furanone is extant in enormous quantity in biologically active substances, such as natural products^22,23, pharmaceutical agents ^24,25, and in medication chemistry. Hydrogenated 2(5H)-furanone compounds have significant interest due to their biological significance and synthesis simplicity ^26–29 especially, the 4-arylamino-2(5H)-furanone structure is a regarded significant template for the synthesis of novel medicines^30–32. Furthermore, there have been reports of symmetrically benzidine derivatives having an identical biological moiety at every terminus that exhibits excellent biological activities, including antiviral^33,34, and anti-tumor³⁵, because of the better sensitivity of the amino groups in both ends of the molecule ^36–38. However, the preparation of bis-2(5H)-furanone compounds with a benzidine core as potentially medicinal compounds has not been reported ^39–42. From the above facts, our concern is synthesizing and evaluating them for their biological activities. We focused in this study on the preparation, DFT study, and pharmacological evaluation of a novel chain of furan-2(3H)-one that could serve as a novel and promising scaffold in breast and liver candidates.

Results and Discussion

1.1. Chemistry

The target beginning substance was L which was prepared by the reaction of the piperonal with β-benzoyl propionic acid in a mixture of fused sodium acetate in acetic anhydride on a boiling water bath for 3 hours. As stated in a reported process ⁴³. Lactone L reacts with ethyl cyanoacetate in a solution of ethyl alcohol and ammonium under ultrasonic irradiation yielded (2E, 5Z, 6Z).-ethyl-2-amino-5-(benzo[d][1,3]dioxol-5-ylmethylene)-4-oxo-7-phenyl-4,5-dihydro-1H-azepine-3-carboxylate (L1). The IR chart of L1 shows peaks at ´υ 3427, 1750, 1684cm^− 1 according to NH₂, NH, and 2CO (amide, ester) groups, respectively ^44,45. ¹H-NMR spectrums of L1 presented signals at δ 2.03, 3.3, 10.46 ppm for NH₂, =CH azepine, NH groups, respectively. ¹³CNMR spectrum of L1 Also take into consideration azepine-3-carboxylateform. The reaction of lactone (L) with ethyl acetoacetate and/ or acetylacetone in ethyl alcohol and sodium hydroxide produced (2E,5Z,6Z)-ethyl-5-(benzo[d][1,3]dioxol-5-ylmethylene)-2-methyl-4-oxo-7-phenyl-4,5-dihydrooxepine-3-carboxylate (L2) and (2Z,5Z,6Z)-3-acetyl-5-(benzo[d] [1,3] dioxol-5-ylmethylene)-2-methyl-7-phenyloxepin-4(5H)-one (L3) with high yields, respectively. The two compounds' structures were interpreted using elemental and spectral analysis. ¹H NMR spectrum of L2 accounts for two signals at δ 4.2 and 1.13 ppm for CH₂ and CH₃ of the ethyl group additionally a singlet signal of the methyl moiety at δ 2.3 ppm, respectively. However, the ¹H-NMR pattern of L3 exposed two signals at δ 2.05 and 1.02 ppm attributed for two CH₃ acetyl and methyl groups respectively. The reaction of the lactone (L) with ethylenediamine in DMF under MW radiation or in ethyl alcoholic potassium hydroxide under ultrasonic irradiation gives L4 were obtained by yield(95%) in MW and (88%) in ultrasonic. The constructions of compound L4 were elucidated by IR, ¹HNMR, and Mass spectroscopy which are consistent with their structure. ¹H-NMR revealed signals at δ 1.0 for the NH₂ group (D₂O exchangeable) 3.17 and 2.79 ppm for two CH₂ groups respectively additionally a singlet signal of the pyrole at δ 3.7 ppm (cf. Experimental part and Scheme 1).

Conversely, compound L was irradiated under the microwave (MW) or ultrasonic with thiosemicarbazide, semicarbazide, urea or thiourea furnished carbothioamide derivative (L5), 3, 4-dihydropyridine-1 (2H)-carboxamide derivative (L6), 7-phenyl-1H-1,3-diazepin-2(5H)-one (L11) and L12 respectively. We observed a higher yield of products from MW than those produced using ultrasound. The structures of compounds L5, L6, L11, and L12 were elucidated using elemental analyses, FTIR, ¹H-NMR, ¹³C-NMR, and MS that are matched with their constructions. (cf. Experimental section and Scheme 2).

The IR chart of (L5) displayed bands at ´υ 3419 − 3165, 1684, 1246 cm^− 1 attributed to (NH₂ and NH, D₂O exchangeable), (CO amide), (C = S) groups ^46,47, respectively. ¹HNMR spectrum of (L5) showed signals at δ: 10.0, 3.41, 1.03 ppm for = CH pyridazine, NH₂, NH (D2O exchangeable) groups, respectively. The IR chart of (L6) displayed bands at ´υ 3472 − 3241, 1690 cm^− 1 attributed to (NH₂ and NH, D₂O exchangeable), (2CO amide) groups, respectively. ¹HNMR spectrum of (L6) revealed signals at δ: 2.4, 3.5, 10.0 ppm for NH₂, =CH pyridazine, NH groups ⁴⁸, respectively. ¹³CNMR spectrum of L6 also account for 3,4-dihydropyridazine-1(2H)-carboxamide form. The IR chart of L11displayed bands at ´υ 3400, 3217, 1718 cm^− 1 realtive to OH, NH, and CO amide moiety, respectively. ¹H NMR of L12 presented two singlet signals at δ9.52, and 9.54 ppm for 2NH groups (D₂O exchangeable). additionally, the MS indicates ion peak MS (m/z): 350 (M.+, 2.22%) which confirms the structure.(Experimental part &Scheme 2).

Finely, compound L was reacted with phenylhydrazine and/or hydrazine hydrate solution in absolute ethyl alcohol afforded (Z)-4-(benzo[d][1,3]dioxols-5-ylmethylene)-1,6-diphenyl-1,2-dihydropyridazine-3(4H)-one (L7) and/or (Z)-4-(benzo[d][1,3]dioxol-5-ylmethylene)-6-phenyl-4,5-dihydropyridazin-3(2H)-one (L8) respectively. The molecular structures of the two substances were deduced by using elemental and spectral studies. IR spectra of L7 showed bands of two NH, CO amide groups at 3286, 1637, 3207, and 1654 cm^− 1 for L8. ¹H-NMR of the two compounds indicated signals for NH (D2O exchangeable), =CH groups at δ9.55, 6.65 ppm for L7 and at 9.55, 5.92 ppm for L8. ¹³NMR and mass spectra also revealed evidence of the two compounds' structures. (cf. Experimental section &Scheme 3). Also, reaction of L with propane-1-amone and/or isoproplamine gave L16, L17 respectively.. ¹H-NMR of L16 showed signals at δ0.69, 1.30, 2.46, 3.22, 6.0, and 7.34 ppm indicated for CH₃, 3 CH₂, =CH and NH (D₂O exchangeable) groups respectively. While ¹H NMR of L17 revealed signals at δ 1.06 2CH₃), 1.35 CH), 2.46 CH₂), 3.3 CH₂CO), 6.6 = CH), 7.54 attributed to 2CH₃, CH), CH₂), CH₂CO), =CH) and NH (D₂O exchangeable) groups respectively. ¹³C NMR and MS indicated the configurations of the two substances.

LN was produced by the reaction of L with dry ammonia in ethyl alcohol. Mannich reaction of LN with formaldehyde/pipridine solution afforded L19 in good yield. IR chart of LN displayed peaks at 3428 and 1685 (NH) and (CO, amide); ¹H-NMR chart of the same substance display signals at δ 2.46, 3.34, and 10.46 ppm for CH₂, 1,3-dioxol, =CH pyrrole) and NH (D₂O exchangeable) groups respectively. While, ¹H NMR of L19 revealed signals at δ 0.85 − 0.82, 1.02, 1.24–1.1 ppm for piperidine 5CH₂ in addition to signals at δ 2.46,3.3, 4.10, and 6.08 ppmattributed for CH₂, 1,3-dioxol,=CH pyrrol, NCH₂N and CH groups respectively. Mass spectra showed evidence of the structures of the two compounds (cf. Experimental section and Scheme 3).

2.2. InVitroAntiproliferative activities

Thirteen prepared materials (anticancer inhibitor) were investigated in vitro for their capability to prevent human cancer cells, namely HCT-116, HepG2, and MCF-7, as well as one human healthy cell line, BJ-1 utilizing the LDH analyze. We computed and compared the proportions of dead cells to those of the control. The efficiency of these inhibitors versus three cancer cell lines was relative to those of doxorubicin. Three cancer cells (HCT-116, HepG2, and MCF-7) were inhibited using the prepared materials in a dose-dependent way Figures (1– 3). In the case of HCT-116 human colorectal carcinoma cells: Fig. 1 & Table 1 display that four inhibitors (L4, LN, L5, and L3, respectively) have slightly less cytotoxic activities; the remaining inhibitors have moderate cytotoxic activities towards HCT-116 comparable to that of doxorubicin. Furthermore, one compound (LN) exhibit superior cytotoxic efficiency against MCF-7 human breast cancer cells, whereas L4, and L3, respectively) have slightly less cytotoxic effects. The remaining inhibitors have moderate cytotoxic activities towardMCF-7 compared to the reference drug (Fig. 2 & Table 1). In the instance of HepG2 human liver cancer cells: eight inhibitors (L1, L3, L4, L19, L2, L16, L12 and L8, respectively) have superior cytotoxic efficiency; four inhibitors (L6, LN, L7 and L17, respectively) have slightly less activities; one compound (L5) has moderate cytotoxic efficiency toward HepG2 relative to that of doxorubicin (Fig. 3 & Table 1). In the instance of the non-tumor fibroblast-derived cell line (BJ): Fig. 4 and Table 1 display that ten inhibitors (L7, L17, L12, L6, LN, L16, L19, L8, L1 and L4, respectively) have superior cytotoxic activities; one compound (LN) has slightly less cytotoxic efficiency; L2 and L5 have feeble cytotoxic efficiency toward the healthy cells compared to that of doxorubicin.

By evaluating the cytotoxicity data on each kind of cancer compared to a normal cell line, one may accomplish that: five inhibitors (L1-L5) could be considered as good selective anticancer candidate drugs for only human liver cancer as their effect on this cancer type is much more toxic compared to their toxicity on the human healthy cells.

Table 1

The anti-proliferative IC₅₀ of the thirteen prepared materials toward the four cell lines agreeing to the LDH analyze
Compound Code	IC₅₀ (µM) ± SD
Compound Code	HCT-116	HepG-2	MCF-7	BJ-1
(L1)	21.1 ± 2.1	1.3 ± 0.1	19.2 ± 1.3	3.9 ± 0.1
(L2)	27.5 ± 2.13	3.1 ± 0.1	17.2 ± 1.4	14.8 ± 1.1
(L3)	15.5 ± 1.1	2.2 ± 0.1	6.3 ± 0.4	9.3 ± 0.7
(L4)	12.6 ± 1.1	2.9 ± 2.1	5.3 ± 0.4	6.2 ± 0.3
(L5)	14.8 ± 1.2	9.8 ± 0.3	12.6 ± 1.1	29.5 ± 3.2
(L6)	24.1 ± 2.3	4.9 ± 0.2	21.6 ± 2.1	2.9 ± 0.1
(L7)	29.2 ± 2.2	5.9 ± 0.3	28.5 ± 2.4	1.7 ± 0.1
(L8)	27.5 ± 2.2	4.3 ± 0.2	34.4 ± 13.2	3.3 ± 0.1
(L12)	26.1 ± 12.3	3.9 ± 0.2	31.8 ± 3.2	1.8 ± 0.1
(L16)	25.7 ± 2.5	3.7 ± 0.2	28.1 ± 2.9	2.9 ± 0.1
(L17)	20.8 ± 2.1	6.5 ± 0.2	26.9 ± 2.3	1.5 ± 0.1
(L19)	20.9 ± 2.1	3.1 ± 0.1	9.8 ± 0.6	3.1 ± 0.1
(LN)	13.7 ± 1.1	5.7 ± 0.2	2.6 ± 0.1	2.1 ± 0.1
Doxorubicin	12.3 ± 1.2	4.4 ± 0.2	3.3 ± 0.1	6.2 ± 0.4

DFT using quantum chemical computations describes the structural optimization of the desired products. The higher E_HOMO indicates a strong molecule tendency to donate electrons that lead to lower ΔE giving good inhibition efficiencies ^39–41.The hardness, dipole moment, softness, surface area (nm²),and recently identified pyrrolone arylidene derivatives with hydrophobic moiety were shown to be an outstanding explanation for their anticancer activity ⁴⁹. The Ionization potential (I, eV), transmitted electrons, and the density of charge distributions (ΔN) show that pyrrolone derivatives L3, L4, LN, and azapyrrolone L5 (pyrimidinone) have the highest transfer of electrons for inhibiting cancer cells. The optimization configurations of the bioactive pyrrolone derivativesas outlined in (Fig. 5 and Table 2) are in great accordance with the anticancer activities L4 < LN < doxorubicin. Small ΔE values, electron distributions, number of hetero-atoms, surface area, and lipophilicity are mentioned in soft inhibitors, having more active to radical surface interactions means talented electron donating readily to hole the surface and scavenge capacity toward the positive hole, radical, tumor, and oxygen removed ^42–44.

Table 2

Global reactivity indices and energy level distribution of frontier orbitals.
Compound	E_HOMO	E_LUMO	ΔE	I^a	A^b	µ^c	η^d	ω^e	ΔN^f	S^g	A_molec(nm²)
L1	-2.55	-1.03	1.52	2.11	4.22	3.30	0.63	40.02	0.045	2.33	311.435
L2	-2.82	-1.12	1.70	2.11	5.34	5.45	0.76	35.65	0.076	1.99	400.276
L3	-3.63	-2.60	1.03	3.01	3.85	5.76	0.84	33.42	0.083	1.54	393.846
L4	-3.80	-3.53	0.27	3.03	2.77	4.88	0.93	30.22	0.069	1.56	430.256
L5	-3.82	-3.77	0.15	3.11	2.87	1.78	1.53	11.70	0.085	0.65	340.559
L19	-3.36	-1.82	1.54	2.55	3.76	2.40	0.75	28.09	0.35	1.33	399.099
LN	-1.75	-1.70	0.05	2.56	3.22	2.56	0.78	26.04	0.77	3.24	417.625
DOX	-1.69	-1.51	0.18	2.38	3.21	2.51	0.75	25.65	0.86	3.12	416.777

From computational platforms to predict properties of some interesting synthesized inhibitors L4 and L19 via admetSAR 2.0 ⁵⁰ that outlined in the Table 3. The presence of piperidine precursor in the drug L19 could be increased the cytotoxicity and become ready biodegradable as compared with drug L4. The author can be concluded the attendance of the amino group in the drug L4 decreased its efficiency due to inhibit cytochrome P450 (CYP 2C9). The presence of a piperidine moiety at the side chain's terminals end of a conjugated double bond makes it excellent for influencing the microsomal oxidation of a wide range of prepared materials.

In general, these piperidine analogs' SAR demonstrates that two factors can be used to control PPARa/c binding affinity and functional activity: (a) changing the oxyphenyl substitutions (1,3 vs. 1,4 series); and (b) the linker (m = 0–2) that connects the oxyphenyl and piperidine ring. ⁵¹

Table 3 Outline the result and probability for ADME of the drug L4 (left) and drug L19 (right)

4.1. Chemistry

The instruments utilized for melting point, elemental analysis, and spectra data

(FTIR, ¹H NMR, ¹³C NMR, and X ray diffraction) are described in depth in the Supplementary information

4.1.1. Preparation of L

A mixture of the piperonal (1.2 moles), β-benzoyl propionic acid (1 mole), and fused sodium acetate (1mole) in acetic anhydride (10 ml) were heated using a water bath for three hours and then left overnight. The decomposition of acetic anhydride with ice-water precipitated a solid product which filtrate, was washed using a mixture from 10% sodium carbonate, then washed with water, dried under vacuum, and finally crystallized form was obtained lactone (L) using a suitable solvent.

4.1.2. Preparation of L1

A mixture of the lactone L (0.5 gram, 0.01 mole), ethyl cyanoacetate (0.4 gram, 0.01 mole), and (0.15 gram, 0.002 mole) ammonium acetate was dissolved in ethanol (30 ml). The mixture was refluxed for one hour using ultrasonic irradiation, after cooling; the obtained yield was filtered, rinsed with deionized water, dried, and the recrystallization process takes place using ethyl alcohol to produce the substance L1. Brown powder; yield 96%, melting point 176–178^◦C; FTIR (Potassium bromide): ´υ/cm^− 1:3427 (NH₂, NH), 1750 (CO, ester), 1684 (CO, amide); ¹H- NMR: δ 1.02–0.99 (t, 3H, CH₃), 2.52–2.46 (q, J = 6.0 Hz, 2H, CH₂), 2.03 (s, 2H, NH₂, D₂Oexchangeable), 2.46 (s, 2H, CH₂, 1,3-dioxol), 3.3 (s, 1H, =CH, azepine), 6.08 (s, 1H, =CH), 6.98–6.87 (m, 5H, Ar-H), 7.85–7.4 (d, J = 2.4, 2H, Ar-H), 7.86 (s, 1H, Ar-H); 10.46 (s, 1H, NH, D₂Oexchangeable);¹³C NMR δ: 26, 97, 102, 109.3, 109.6, 126–130, 145,148,149, 171.6; MS (m/z): 404 (M.+, 22.36%); Analytical calculation for (C₂₃H₂₀N₂O₅): C, 68.29; H, 4.99; N, 6.95; Found: C, 68.36; H, 5.02; N, 6.97

4.1.3. Preparation of L2

Lactone L (0.5 gram, 0.01 moles) and ethyl acetoacetate (0.4 gram, 0.01 mole) were dissolved in 30 ml of ethyl alcoholhaving 1 ml of 10% aqueous KOH. The mixture was refluxed for one hour under ultrasonic irradiation and kept at ambient temperature for 12 hours. The obtained yield precipitate was filtered, air-dried, and the recrystallization process takes placeethyl alcohol, yielding the substance L2. Dirty yellow powder; yield 96%, melting point. 278–280^◦C; FTIR (Potassium bromide): ´υ/cm^− 1:1750, 1684 (2CO); ¹H NMR (ppm): δ 1.13–1.11 (t, J = 6.1, 3H, CH₃CH₂), 2.3 (s, 3H, CH₃), 2.60 (s, 2H, CH₂, 1,3-dioxol), 3.3 (s, 1H, =CH, oxepine), 4.22–4.08 (q, J = 6.5, 2H, CH₃CH₂CO), 6.01 (s, 1H, =CH), 6.92–6.88 (m, 5H, Ar-H), 7.76–7.52 (d, J = 2.4, 2H, Ar-H), 8.02 (s,1H, Ar-H); MS (m/z): 404 (M.+, 12.36%); Anal. calc. for (C₂₄H₂₀O₆): C, 71.28; H, 4.98%; Found: C, 71.31; H, 5.03%.

4.1.4. Preparation of L3

A mixture of the lactone L (0.5 gram, 0.01 moles), acetylacetone (0.4 gram, 0.01mole) in absolute ethyl alcohol, and NaOH (15 ml, 50%) was heated under refluxed condition for one hour using ultrasonic irradiation, and then kept for 12 h at ambient temperature. After that pour the mixture onto ice water and then acidified with concentrated hydrochloric acid to get a solid which was recrystallized from dioxane to obtain substance L3. Deep brown powder; yield 89%, melting point. 154–156^◦C; FTIR (Potassium bromide): ´υ/cm^− 1:1750, 1705 (2CO); 1H NMR (ppm): δ 1.02 (s, 3H, CH₃), 2.05 (s, 3H, CH₃CO), 2.60 (s, 2H, CH₂, 1,3-dioxol), 3.38 (s, 1H, =CH, oxepin), 5.92 (s, 1H, =CH), 7.11–6.78 (m, 5H, Ar-H), 7.49–7.46 (d, J = 2.4, 2H, Ar-H);7.92 (s,1H, Ar-H); MS (m/z): 374 (M.+, 31.11%); Anal. calc. for (C₂₃H₁₈O₅): C, 73.79; H, 4.85%; Found: C, 73.84; H, 4.89%.

4.1.5. Preparation L4

A mixture of lactone L (0.5 gram, 0.01 moles) and ethylenediamine (0.4 gram, 0.01 mole) in dimethylformamide was irradiated using microwave radiation for 1 min. or under-refluxed for one hour using ultrasonic irradiation in ethyl alcohol containing aqueous KOH (50 ml, 4%). After that pour the mixture onto ice water and then change pH of the medium to acidic form using concentrated hydrochloric acid to get a solid precipitate which was recrystallized from ethyl alcohol to give compound L4. Brown powder; yield (95%) in microwave, but (88%) in ultrasonic, melting point 150–152^◦C; FTIR (Potassium bromide): ´υ/cm^− 1:3419 (NH₂), 1674 (CO amide); ¹H NMR: 1.0 (s,2H, NH₂), 2.80–2.79 (t, J = 7.15, 2H, CH₂), 3.17–2.95 (t, 2H, CH₂), 6.07 (s, 2H, CH₂, 1,3-dioxol), 3.7 (s, 1H, =CH pyrrol), 6.1 (s, 1H, =CH), 7.0–7.54 (m, 5H, Ar-H), 7.6–7.7 (d, J = 2.4, 2H, Ar-H);MS (m/z): 334 (M.+, 2.11%); Anal. calc. for (C₂₀H₁₈N₂O₃): C, 71.84; H, 5.43; N, 8.38%; Found: C, 71.89; H, 5.47; N, 8.43%.

4.1.6. General procedure for preparing inhibitors L5, L6, L11 & L12

Firstly, lactone L (3.4 gram, 10 mmol) was dissolved in ethyl alcohol containing aqueous KOH (50 ml, 4%). Then, the solution was mixed with thiosemicarbazide, semicarbazide, urea, or thiourea (10 mmol). The reaction mixture was irradiated either by microwaves for one minute or ultrasonically refluxed for one hour. The solvent was eliminated by reducing the pressure, and the solution of reaction was put into acidic water. Finally, the solid precipitate was recovered by filtering, rinsed with water, and the recrystallization process takes place in the appropriate solvent to yield substances L5, L6, L11, and L12, respectively.

4.1.6.1. Spectroscopic data of L5

Brick red powder, the recrystallization process takes place using isopropyl alcohol.; yield (93%) in microwaves and (82%) in ultrasonic, melting point 77–81^◦C; FTIR (Potassium bromide): ´υ/cm^− 1:3419 − 3165 (NH₂ and NH), 1684 (CO amide), 1246 (C = S); ¹H-NMR (ppm): 1.03 (s, 2H, NH₂), 2.47 (s, 2H, CH₂, 1,3-dioxol), 3.41 (s, 1H, =CH pyridazine), 5.90 (s, 1H, =CH), 6.81–6.67 (m, 5H, Ar-H), 7.87–7.35 (d, J = 2.3, 2H, Ar-H), 7.87 (s,1H, Ar-H),10.0 (s,1H, NH); MS (m/z): 364 (M.+, 4.18%); Anal. calc. for (C₁₉H₁₅N₃O₃S): C, 62.52; H, 4.21; N, 11.49%; Found: C, 62.49; H, 4.21; N, 11.54%.

4.1.6.2. Spectroscopic data L6

Yellow powder, recrystallization process takes place using isopropyl alcohol; produce 92% by using microwaves irradiation but in case of using ultrasonic the obtained yield was 81%, m.p. 136–138^◦C; FTIR (Potassium bromide): ´υ/cm^− 1:3472 − 3241 (NH₂ and NH), 1690 (2CO amide); ¹H NMR (ppm): 2.4 (s,2H, NH₂), 2.47 (s, 2H, CH₂, 1,3-dioxol), 3.56 (s, 1H, =CH pyridazine), 5.80 (s, 1H, =CH), 6.80–6.69 (m, 5H, Ar-H), 7.55–7.33 (d, J = 2.4, 2H, Ar-H), 7.51 (s, 1H, Ar-H), 10.0 (s,1H, NH, D₂Oexchangeable); ¹³C NMR δ: 35, 40, 69, 73, 101, 109, 126, 128, 137, 146, 155, 157, 164, 173, 177, 188; MS (m/z): 349 (M.+, 14.65%); Anal. calc. for (C₁₉H₁₅N₃O₄): C, 65.29; H, 4.35; N, 12.1%; Found: C, 65.39; H, 4.38; N, 12.08%.

4.1.6.3. Spectroscopic data of L11

Deep brown powder, the recrystallization process proceeded using absolute ethyl alcohol; produced 95% by using microwave irradiation but in the case of using ultrasonic the obtained yield was 88%, m.p. 88–90^◦C; IR chart (Potassium bromide): ´υ/cm^− 1:3400 (OH), 3217 (NH), 1718 (CO, amide); ¹H NMR ( (ppm): 2.46 (s, 2H, CH₂, 1,3-dioxol), 3.40 (s, 1H, =CH diazepin), 5.94 (s, 1H, =CH), 7.40–7.33 (m, 5H, Ar-H), 7.91–7.45 (d, J = 2.4, 2H, Ar-H), 7.92 (S, 1H, Ar-H), 9.0 (s,1H, NH), 10.92 (s, 1H, OH): MS (m/z): 334 (M.+, 20.15%); Analytical calculation. for (C₁₉H₁₄N₂O₄): C, 68.27; H, 4.31; N, 8.41%; Found: C, 68.31; H, 4.28; N, 8.42%.

4.1.6.4. Spectroscopic data of L12

Pale yellow powder, the recrystallization process happens to utilize absolute ethyl alcohol; the yield was 91% by using microwave irradiation but in the case of using ultrasonic the obtained yield was 80%, m.p. 85–87^◦C; FTIR (Potassium bromide): 3217 − 3195 (2NH), 1699 (CO, amide), 1244 (C = S), ´υ/cm^− 1:1H-NMR (ppm): 2.46 (s, 2H, CH₂, 1,3-dioxol), 3.31 (s, 1H, =CH diazepine), 5.22 (s, 1H, =CH), 6.86–5.96 (m, 5H, Ar-H), 7.35–7.27 (d, J = 2.4, 2H, Ar-H), 7.37 (s, 1H, Ar-H), 9.52, 9.54 (s, 1H, 2NH, D₂O exchangeable); MS (m/z): 350 (M.+, 2.22%); Analytical calculation. for (C₁₉H₁₄N₂O₃S): C, 65.13; H, 4.03; N, 7.99%; Found: C, 65.18; H, 4.08; N, 8.03%.

4.1.7. General preparation method for substances L7 and L8

lactone L (3.4 g, 10 mmol) was mixed with phenylhydrazine (5 ml, 0.01 mol) in ethyl alcohol (10 ml) having glacial acetic acid (0.5 ml). The reaction solution was exposed to irradiation either by microwave1 for a minute or using ultrasonic reflux irradiation for one hour. The reaction solution was placed onto ice water after the solvent was eliminated using low pressure. The resultant yield was filtered, collected, and then cleaned with water before being recrystallized in the appropriate solvent to yield substances. L7 and L8 respectively.

4.1.7.1. Spectroscopic data of L7

Brick red powder; the recrystallization process proceeded using isopropyl alcohol; produce 90% by using microwaves irradiation, but in case of using ultrasonic the obtained yield was 78%, m.p. 103–105^◦C; FTIR (Potassium bromide): ´υ/cm^− 1: 3286 (NH), 1637 (CO, amide); ¹H NMR (ppm): 2.46 (s, 2H, CH₂, 1,3-dioxol),3.3 (s, 1H, =CH pyridazine), 6.65 (s, 1H, =CH), 6.66–6.65 (m, 5H, Ar-H), 7.15–7.07 (m, 5H, Ar-H), 7.59 (d, J = 2.4, 2H, Ar-H), 7.59 (s, 1H, Ar-H), 9.55 (s,1H, NH, D₂O exchangeable); ¹³C NMR δ: 21, 40, 89, 101, 109, 110, 122, 126, 128, 129, 143, 147, 161; MS (m/z): 382 (M.+, 3.9%); Anal. calc. for (C₂₄H₁₈N₂O₃): C, 75.39; H, 4.69; N, 7.31%; Found: C, 75.41; H, 4.79; N, 7.38%.

4.1.7.2. Spectroscopic data of L8

Orange powder; the recrystallization process proceeded using absolute alcohol; yielding 95% by using microwaves irradiation, but in the case of using ultrasonic the obtained yield was 90%, m.p. 150–153^◦C; FTIR (Potassium bromide): ´υ/cm^− 1: 3207 (NH), 1654 (CO, amide); ¹H-NMR (ppm): 2.4 (s, 2H, CH₂, 1,3-dioxol), 3.31 (s, 2H, CH₂ pyridazine), 5.92 (s, 1H, =CH), 7.32–6.79 (m, 5H, Ar-H),7.45–7.39 (d, J = 2.4, 2H, Ar-H), 7.81 (s, 1H, Ar-H), 9.55 (s, 1H, NH, D₂O exchangeable); 13C NMR δ: 39, 89, 101, 108, 110, 122, 126, 129, 143, 146, 147, 161; MS (m/z): 306 (M.+, 20.3%); Anal. calc. for (C₁₈H₁₄N₂O₃): C, 70.60; H, 4.59; N, 9.09%; Found: C, 70.63; H, 4.66; N, 9.19%

4.1.8. General preparation method of substances L16 and L17

A solution of lactone L (3.4 g, 10 mmol) and propyl amine (5 ml, 0.01 mol) or isopropyl amine (5 ml, 0.01 mol) in DMF. Microwave (MW) irradiation was applied to the reaction mixture and left for one minute. On top of the ice water, the solution was added. The resultant precipitation was filtered, collected, and then cleaned with water before being recrystallized in the appropriate solvent to yield substances L16 and L17 respectively.

4.1.8.1. Spectroscopic data of L16

Deep brown powder; recrystallized from benzene; yield (95%) in MW, m.p. 138–140^◦C; FTIR (Potassium bromide): ´υ/cm^− 1: 3278 (NH), 1755 (C = O, ketone), 1678 (C = O, amide); ¹H-NMR ( (ppm): 0.69 − 0.66 (t, 3H, CH₃), 1.25 (m, 2H, CH₂), 1.39 (t, 2H, CH₂), 2.46 (s, 2H, CH₂, 1,3-dioxol), 3.22 (s, 2H, CH₂CO), 6.0 (s, 1H, =CH), 7.04–6.62 (m, 5H, Ar-H),7.34–7.18 (d, J = 2.4, 2H, Ar-H), 7.33 (s, 1H, Ar-H), 7.34 (s, 1H, NH, D₂O exchangeable); ¹³C NMR δ: 12, 22, 39, 40, 89, 101, 109, 128, 128, 129, 144, 148, 168; MS (m/z): 351 (M.+, 20.3%); Analytical calculation. for (C₂₁H₂₁NO₄): C, 71.8; H, 6.02; N, 3.99%; Found: C, 71.71; H, 6.01; N, 3.94%.

4.1.8.2. Spectroscopic data of L17)

Brown powder; the recrystallization process proceeded using benzene; produce (94%) in microwaves irradiation, m.p. 139–141^◦C; FTIR (Potassium bromide): ´υ/cm⁻1: 3278 (NH), 1757 (C = O, ketone), 1675 (C = O, amide); ¹H-NMR (ppm): 1.06–1.01 (d, 6H, 2CH₃), 1.35–1.1 (septet, 1H, CH), 2.46 (s, 2H, CH₂, 1,3-dioxol), 3.3 (s, 2H, CH₂CO), 6.6 (s, 1H, =CH), 7.25-7.0 (m, 5H, Ar-H), 7.47–7.38 (d, J = 2.4, 2H, Ar-H), 7.47 (s, 1H, Ar-H), 7.45 (s, 1H, NH, D₂O exchangeable);¹³C NMR δ: 21, 90, 101, 109, 125, 126, 128, 129, 135, 144, 148, 150, 155, 167;MS (m/z): 351 (M.+, 8.3%); Anal. calc. for (C₂₁H₂₁NO₄): C, 71.8; H, 6.01; N, 3.98%; Found: C, 71.82; H, 6.06; N, 4.02%.

4.1.9. Preparation of LN

An anhydrous ethyl alcoholic solution of lactone L (1.0 g) was circulated through dry ammonia gasfor one hour to obtain the product LN, the ethyl alcohol was distilled out at ambient temperature under low pressure and then recrystallized from methyl alcohol and acetone. Brick red powder; produce (96%), melting point. 120–122^◦C; FTIR (Potassium bromide): ´υ/cm^− 1: 3428 (NH), 1690 (CO, amide); ¹H NMR (ppm): 2.46 (s, 2H, CH₂, 1,3-dioxol),3.34 (s, 1H, =CH pyrrol), 6.08 (s, 1H, =CH), 6.98–6.87 (m, 5H, Ar-H), 7.45–7.40 (d, J = 2.4, 2H, Ar-H), 7.86 (s, 1H, Ar-H), 10.46 (s,1H, NH); MS (m/z): 291 (M.+, 4.13%); Analytical calculation of (C₁₈H₁₃NO₃): C, 74.22; H, 4.50; N, 4.81%; Found: C, 74.26; H, 4.53; N, 4.85%.

4.1.10. Preparation of L19

A mixture of lactam LN (0.5 g, 0.01 mol) in ethyl alcohol (25 ml) was introduced to formaldehyde (1.5 ml, 40%), and then solution was refluxed under ultrasonic irradiation for one hour and then cooled. After adding piperidine (0.01 mol) drop wise, the reaction solution was agitated for five hours. The precipitated material was separating from the ethyl alcohol by filtering, drying, and recrystallization to produce the substance L19. Deep brown powder; yield (80%), melting point 134–136^◦C; FTIR (Potassium bromide): ´υ/cm^− 1: 2918 (CH₂, aliphatic), 1690 (CO, amide); ¹H NMR (ppm): 0.85-.082 (m, 2H, CH₂, piperidin), 1.02 (m, 4H, 2CH₂, piperidin), 1.24–1.1 (t, 4H, 2CH₂N, piperidin), 2.46 (s, 2H, CH₂, 1,3-dioxol),3.3 (s, 1H, =CH pyrrol), 4.10 (s, 2H, NCH₂N), 6.08 (s, 1H, =CH), 7.38–6.88 (m, 5H, Ar-H), 7.85–7.40 (d, J = 2.4, 2H, Ar-H), 7.86 (s, 1H, Ar-H); MS (m/z): 390 (M.+, 11.33%); Anal. calc. for (C₂₄H₂₄N₂O₃): C, 74.25; H, 6.25; N, 7.20%; Found: C, 74.26; H, 6.27; N, 7.25%.

4.2. In vitroAnti-proliferative Activities:

4.2.1. Cell culture

The cell lines were kept in RPMI-1640 medium supplementary with 10% heat-inactivated FBS, 100U/ml penicillin, and 100U/ml streptomycin. The cells were cultured in a humidified environment with 5% CO₂ at 37°C. Each experiment was performed three times in duplicate (n = 3). Each value was shown as the mean ± standard deviation.

4.2.2. Lactate dehydrogenase (LDH) analyzed

LDH releasing experiment was utilized to ascertain the impact of each produced chemical on the permeability of the membrane in the HepG2, MCF-7, and HCT-116 cancer cell lines and in the BJ-1 normal cell line ^52–54. Before treatment, the cells were permitted to proliferate for 18 hours in 24-well plate cultures at a density of 2 × 105 cells/well in 500 µL volume. The plates were treated for 48 hours with a range of concentrations of every substance or Doxorubicin (positive control) ⁵⁵.

4.2.3. Statistical analysis

Each study was performed in triplicate (n = 3). All values were expressed as mean ± SD. Significant variations in parameter mean and IC50s were evaluated using probit analysis with the SPSS software package (SPSS Inc., Chicago, IL).

Thirteen new heterocyclic inhibitors (L1-L19) were synthesized from the green reaction of (Z)-3-(benzo[d][1,3]dioxol-5-ylmethylene)-5-phenylfuran-2(3H)-one (L) with different electrophilic and nucleophile reagents like ethylcyanoacetate, ethylacetoacetate, acetlacetone, ethane-1,2-diamine, thiosemicarabazide, hydrazinecaroxamide, urea, thiourea, phenlhydrazine, hydrazine hydrate, propylamine, isoproplamine and/or dry ammonia/ethyl alcohol under ultrasonic irradiation. The novel substances were examined for their in vitro ant proliferative efficiency toward HepG-2, HCT116, MCF-7, and the normal human skin fibroblast (BJ-1) cell lines. The results showed that five inhibitors (L1- L5) have promising selective cytotoxic activities toward the human liver cancer type. DFT Study of the newly synthesized inhibitors showed that pyrrolone derivatives L3, L4, LN, and azapyrrolone L5 (pyrimidinone) have the maximum electron transfer for inhibition for cancer cells.

ABBREVIATIONS	Definition
BC	Breast cancer
LDH	lactate dehydrogenase
DFT	Density functional theory
MW	Microwave
ADME	Absorption, Distribution, Metabolism and Exertion
SAR	Structure Activity Relationship

Acknowledgment

The authors extend their appreciation to Taif University, Saudi Arabia, for supporting this work through the TU-distinguished scientific publishing program and international appearance, Project number (TU-DSPP-2024-265).

Author Contributions

Synthesis and experimental analysis, E.M.A and W.H.L, Biological evaluation, H.M.A., Computational studies, S.A.R., Writing original draft preparation and editing, E.M.A, H.M.A., and E.A.M.,Amal A. Altalhi, and I.F.N. Reviewing, E.M.A and E.A.M., and I.F.N. All Authors have read and agreed to the published version of the manuscript.

Author information

Eman M. Azmy ([email protected]). Eslam A. Mohamed ([email protected]) Egyptian Petroleum Research Institute, Nasr City, Cairo, Egypt BO-11727, Amal A. Altalhi ([email protected]), Ibrahim F. Nassar ([email protected]),Sameh A. Rizk ([email protected]), Hanem M. Awad ([email protected]), Walaa H. Lashin ([email protected])

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding Information

Authors state no funding is involved

Supporting Information

The supporting information included the instruments utilized for melting point, elemental analysis, and spectra data of FTIR, ¹H-NMR,¹³C-NMR, and X-ray diffraction.

Availability of data and material

Our manuscript has data included as supplementary materials, should be contacted if someone wants to request the data from this study.

Ethics approval

Author (s) pledge that they have familiarized themselves with publishing ethics responsibilities and that hereby they have followed them

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Schemes 1-3 are available in the Supplementary Files section.

No competing interests reported.

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Novel Furan-2(3H)-one derivatives as promising anticancer agents against liver and breast cancers cell lines: Green Synthesis, Spectroscopic analysis, in Vitro Antiproliferative Activity, and DFT study

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Abstract

Figures

1. Introduction

1.1. Chemistry

2.2. InVitroAntiproliferative activities

2. DFT Study

3. Structure Activity Relationship (SAR)

4. Experimental

4.1. Chemistry

4.1.1. Preparation of L

4.1.2. Preparation of L1

4.1.3. Preparation of L2

4.1.4. Preparation of L3

4.1.5. Preparation L4

4.1.6. General procedure for preparing inhibitors L5, L6, L11 & L12

4.1.6.1. Spectroscopic data of L5

4.1.6.2. Spectroscopic data L6

4.1.6.3. Spectroscopic data of L11

4.1.6.4. Spectroscopic data of L12

4.1.7. General preparation method for substances L7 and L8

4.1.7.1. Spectroscopic data of L7

4.1.7.2. Spectroscopic data of L8

4.1.8. General preparation method of substances L16 and L17

4.1.8.1. Spectroscopic data of L16

4.1.8.2. Spectroscopic data of L17)

4.1.9. Preparation of LN

4.1.10. Preparation of L19

4.2. In vitroAnti-proliferative Activities:

4.2.1. Cell culture

4.2.2. Lactate dehydrogenase (LDH) analyzed

4.2.3. Statistical analysis

5. Conclusion

Abbreviations

Declarations

References

Schemes

Additional Declarations

Supplementary Files

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