Abstract In this study, new tetrahydroisoquinoline compounds were synthesized by reaction of 7-Acetyl-4-cyano-1,6-dimethyl-6-hydroxy-8- (3-nitrophenyl or 4-nitrophenyl)-5,6,7,8-tetrahydrosoquinoline-3(2H)-thiones with methyl iodide, chloro acetonitrile, ethyl chloroacetate to produce compounds 3–5 and reacted with N-arylchloroacetamides reagents to gave tetrahydroisoquinolin-3-ylthio) acetamides compounds 6a–c, 8a–b which can cyclized to 6,7,8,9-tetrahydrothieno[2,3-c]Isoquinoline-2-carboxamides compounds 7a–c, 9a–b. Also react with N-(benzthiazol-2-yl)-2-chloroacetamideto give compound 10. The structures of all newly synthesized compounds were characterized by elemental and spectral analyses. Also, most of the synthesized compounds were evaluated for their anticancer activities aganist MCF7 and HEPG2 cell lines. From the result we found that the most active compound against the MCF7 cell lines was compound 8b, and the most active compound against HEPG2 cell lines was compound 3. Then the effects of compound 3 on the HEPG2 cell line was investigated using an apoptotic Annexin V-FITC test and flow cytometry. Compound 3 induced a 59-fold increase in HEPG2 cell line apoptosis and cell cycle arrested at the G0-G1, G2/M phases. Moreover, the molecular docking study was applied and the result showed that compounds 8b bind to the RET enzyme with binding energies of − 6.8 kcal/mol in comparison with standard alectinib, which exhibits a binding energy of − 7.2 kcal/mol. Compound 3 can bind with HSP 90 with a binding energy (ΔG) of − 6.8 kcal/mol, which was comparable to the standard Onalespib (− 7.1 kcal/mol). Graphical Abstract

In this work 7-Acetyl-4-cyano-1, 6-dimethyl-6-hydroxy-8-(2-nitrophenyl)-5,6,7,8-tetrahydrosoquinoline-3(2H)-thione compound 2 was synthesized and used as starting materials. Subsequently, Compounds 3–7 were produced through its reaction with ethyl iodide, ethyl chloroacetate, chloroacetonitrile, and chloroacetaldehyde. Additionally, compound 2 and 2-chloroacetamide were heated in ethanol with sodium acetate trihydrate present, resulting in the formation of 3-Substituted methylthio-5,6,7,8-tetrahydroisoquinoline-4-carbonitriles 9a–d, respectively. Similarly, compounds 2 and N-(1-naphthyl)-2-chloroacetamide reacted to produce high yields of the equivalent N-(1-naphthyl)-(5,6,7,8-tetrahydroiso-quinolin-3-ylthio)acetamides 9e. Compounds 9a–e were cyclized into their 10a and d. Using elemental analysis and spectral data (FT-IR, 1H NMR, and 13C NMR). All newly synthesized compounds were described. The anticancer activity of the produced compounds was also assessed against eight cell lines at one spot concentration and one normal human skin fibroblast cell line HSF. Then determine the IC50 of our drugs against two specific cell lines using various doses. Compound 3 is the most effective chemical against HEGP2, according to our research. Compound 9c was also the most effective compound against HCT116. For generally, the tested substances showed moderate anticancer activity, according to the data. The effects of compound 3 on the proliferation of HEGP2 cell lines were then investigated using an apoptotic Annexin V-FITC assay and flow cytometry. Compound 3 increased the HEGP2 cell line's apoptosis by 50 times and caused cell cycle arrest at the G2/M phase.

In this work, we synthesized new 5, 6, 7, 8-tetrahydroisoquinolines and 6, 7, 8, 9-tetrahydrothieno[2, 3-c]isoquinolines derivatives, and the structures of these new compounds were confirmed with different spectroscopic techniques. Furthermore, the anticancer activities of these compounds were assessed against eight tumor cell lines and one normal human skin fibroblast cell line (HSF). Subsequently, IC50 values of the synthesized compounds were determined for two specific cancer cell lines. Compound 3 exhibited the most potent antiproliferative activity against the HEPG2 cell line, whereas compound 9c demonstrated superior efficacy against the HCT116 cell line. Moreover, the mechanism of action for compound 3 on HEPG2 cells using flow cytometry and Annexin V-FITC apoptosis analysis was studied. Compound 3 caused cell cycle arrest at the G2/M with a 50-fold increase in apoptosis of the HEPG2 cell line. Finally, a molecular docking study was conducted to assess the inhibitory potential of compounds 3 and 7 against the RET enzyme. Results indicated that compounds 3 and 7 bind to the RET enzyme with binding energies of -5.2 and -5.6 kcal/mol, respectively. Although these values suggest inhibitory activity, they are less potent than the standard inhibitor, alectinib, which exhibits a binding energy of -7.2 kcal/mol.

In this study, 7-Acetyl-4-cyano-1,6-dimethyl-6-hydroxy-8- (3-nitrophenyl or 4-nitrophenyl)-5,6,7,8-tetrahydrosoquinoline-3(2H)-thiones 2a-b were synthesized and used as starting materials. Thus, compounds 2a-b were reacted with methyl iodide, ethyl chloroacetate, by heating in ethanol in the presence of sodium acetate trihydrate to give 3-substituted methylthio-5,6,7,8-tetrahydroisoquinoline-4-carbonitriles 3, 4, respectively. In a similar manner, the reaction of compounds 2a-b with N-arylchloroacetamides5a-c afforded the corresponding N-aryl-(5,6,7,8-tetrahydroiso-quinolin-3-ylthio) acetamides 6a-c in excellent yields. In contrast, the reaction of 3b with N-(benzthiazol-2-yl)-2-chloroacetamide (12)under the same (above) conditions yielded 1-amino-N-(benzthiazol-2-yl)-6,7,8,9-tetrahydrothieno[2,3-c]isoquinoline-2-carboxamide13.Cyclization of compounds 6a-c into their 7a-cwas performed by heating in ethanol containing a catalytic amount of sodium ethoxide. The structures of all newly synthesized compounds were characterized by elemental and spectral analyses. Also, most of the synthesized compounds were evaluated for their anticancer activity in MCF7 andHEGP2 cell lines.The most potent compound against theMCF7 cell lines was compound 9b, and the most potent against HEGP2 cell lines was compound 3. Then the effects of compound 3 on the proliferation of HEPG2 cell lines was investigated using an apoptotic Annexin V-FITC test and flow cytometry. Compound 3 induced a 59-fold increase in HEPG2 cell line apoptosis and cell cycle arrested at the G0-G1, G2/M phases.

In this study, we synthesized new 5,6,7,8-tetrahydroisoquinolines and 6,7,8,9-tetrahydrothieno[2,3- c ]isoquinolines based on 4-( N , N -dimethylamino)phenyl moiety as expected anticancer and/or antioxidant agents. The structure of all synthesized compounds were confirmed by spectral date (FT-IR, 1 H NMR, 13 C NMR) and elemental analysis. We evaluated the anticancer activity of these compounds toward two cell lines: A459 cell line (lung cancer cells) and MCF7 cell line (breast cancer cells). All tested compounds showed moderate to strong anti-cancer activity towards the two cell lines. Compound 7e exhibited the most potent cytotoxic activity against A549 cell line (IC 50 : 0.155 µM) while compound 8d showed the most potent one against MCF7 cell line (IC 50 : 0.170 µM) in comparison with doxorubicin. In addition, we examined the effect of compounds 7e and 8d regarding the growth of A549 and MCF7 cell lines, employing flow cytometry and Annexin V-FITC apoptotic assay. Our results showed that compound 7e caused cell cycle arrest at the G2/M phase with a 79-fold increase in apoptosis of A459 cell line. Moreover, compound 8d caused cell cycle arrest at the S phase with a 69-fold increase in apoptosis of MCF7 cell line. Furthermore, we studied the activity of these compounds as enzyme inhibitors against several enzymes. Our findings by docking and experimental studies that compound 7e is a potent CDK2 inhibitor with IC 50 of 0.149 µM, compared to the Roscovitine control drug with IC 50 of 0.380 µM. We also found that compound 8d is a significant DHFR inhibitor with an IC 50 of 0.199 µM, compared to Methotrexate control drug with IC 50 of 0.131 µM. Evaluation of the antioxidant properties of ten compounds was also studied in comparison with Vitamin C. Compounds 1 , 3 , 6 , 7c and 8e have higher antioxidant activity than Vitamin C which mean that these compounds can used as potent antioxidant drugs. Graphical Abstract

In this study, new tetrahydrosoquinoline compounds were synthesized by reacted with methyl iodide, chloro acetonitrile, ethyl chloroacetate, N-arylchloroacetamides N-and (benzthiazol-2-yl)-2-chloroacetamide reagents to gave tetrahydroiso-quinolin-3-ylthio) acetamides (5a-c) which can cyclized to tetrahydroiso-quinolin-3-ylthio) acetamides (6a-c) in excellent yields. The structures of all newly synthesized compounds were characterized by elemental and spectral analyses. Also, most of the synthesized compounds were evaluated for their anticancer activity in MCF7 and HEPG2 cell lines. From the result we found that the most potent compound against the MCF7 cell lines was compound 9b, and the most active against HEPG2 cell lines was compound 3. Then the effects of compound 3 on the HEPG2 cell line was investigated using an apoptotic Annexin V-FITC test and flow cytometry. Compound 3 induced a 59-fold increase in HEPG2 cell line apoptosis and cell cycle arrested at the G0-G1, G2/M phases. Moreover, the molecular docking study was applied and the result showed that compounds 9b bind to the RET enzyme with binding energies of -6.8 kcal/mol in comparison with standard alectinib, which exhibits a binding energy of -7.2 kcal/mol. Compound 3 can bind with HSP 90 with a binding energy (ΔG) of -6.8 kcal/mol, which is comparable to the standard Onalespib (-7.1 kcal/mol).

Regioselective cyclocondensation of 2,4-diacetyl-5-hydroxy-5-methyl-3-(3-nitrophenyl/4-nitrophenyl)cyclohexanones 1a,b with cyanothioacetamide afforded the corresponding 7-acetyl-4-cyano-1,6-dimethyl-6-hydroxy-8-(3- and -4-nitrophenyl)-5,6,7,8-tetrahydrosoquinoline-3(2H)-thiones 2a,b. Reaction of compounds 2a,b with ethyl iodide, 2-chloroacetamide (4a), or its N-aryl derivatives 4b-e in the presence of sodium acetate trihydrate gave 3-ethylthio-5,6,7,8-tetrahydroisoquinoline 3 and (5,6,7,8-tetrahydroisoquinolin-3-ylthio)acetamides 5a-i, respectively. Cyclization of compounds 5b-d,f,g into their isomeric 1-amino-6,7,8,9-tetrahydrothieno[2,3-c]isoquinoline-2-carboxamides 6b-d,f,g was achieved by heating in ethanol containing a catalytic amount of sodium carbonate. Structures of all synthesized compounds were characterized on the basis of their elemental analyses and spectroscopic data. The crystal structure of 5,6,7,8-tetrahydroisoquinoline 5d was determined by X-ray diffraction analysis. In addition, the biological evaluation of some synthesized compounds as anticancer agents was performed, and only six compounds showed moderate to strong activity against PACA2 (pancreatic cancer cell line) and A549 (lung carcinoma cell line). Moreover, the antioxidant properties of most synthesized compounds were examined. The results revealed high antioxidant activity for the most tested compounds.

The title molecule, C 29 H 29 N 3 O 4 S, adopts a conformation with the two phenyl substituents disposed on opposite sides of the mean plane of the isoquinoline unit. In the crystal, corrugated layers of molecules are formed by N—H...O, C—H...N and C—H...S hydrogen bonds together with C—H...π(ring) interactions. These layers are connected by C—H...O contacts. The Hirshfeld surface analysis of the crystal structure indicates that the most important contributions for the crystal packing are from H...H (45.2%), C...H/H...C (20.2%), O...H/H...O (15.8%) and N...H/H...N (11.0%) interactions.