The Design and Cytotoxic Evaluation of Some 1‐Aryl‐3‐isopropylamino‐1‐propanone Hydrochlorides towards Human Huh‐7 Hepatoma Cells

Abstract

A series of 1-aryl-3-isopropylamino-1-propanone hydrochlorides 1 and a related heterocyclic analog 2 as candidate antineoplastic agents were prepared and the rationale for designing these compounds is presented. A specific objective in this study is the discovery of novel compounds possessing growth-inhibiting properties of hepatoma cells. The compounds in series 1 and 2 were prepared and their structures established unequivocally. X-ray crystallography of two representative compounds 1d and 1g were achieved. Over half of the compounds are more potent than 5-fluorouracil which is an established drug used in treating liver cancers. QSAR evaluations and molecular modeling studies were undertaken with a view to detecting some physicochemical parameters which govern cytotoxic potencies. A number of guidelines for amplification of the project have been formulated.

Synthesis of 3-aroyl-4-aryl-1-isopropylamino-4-piperidinols and evaluation of the cytotoxicities of the compounds against human hepatoma and breast cancer cell lines

“…It is possible to find new chemical structures which can be drug candidates by the synthesis and investigation of the cytotoxic activities of semicyclic mono-Mannich bases having piperidine structure namely 3-aroyl-4-aryl-1-isopropylamino-4-piperidinols. Furthermore, it is also possible to observe the alterations in cytotoxicity depending on chemical structures by comparing the cytotoxicities of the compounds reported here with mono-Mannich bases reported in our previous study 13 . Semi-cyclic mono-Mannich bases (piperidines) reported here are non-classic bioisosters of mono-Mannich bases reported before 13 .…”

“…Furthermore, it is also possible to observe the alterations in cytotoxicity depending on chemical structures by comparing the cytotoxicities of the compounds reported here with mono-Mannich bases reported in our previous study 13 . Semi-cyclic mono-Mannich bases (piperidines) reported here are non-classic bioisosters of mono-Mannich bases reported before 13 . In addition, there are not any research about cytotoxic activity of 4-piperidinol derivatives on breast cancer and HCC in the literature.…”

“…It is an advantage and a good starting point that the cytotoxicities of mono-Mannich bases namely 1-aryl-3-isopropylamino-1-propanone hydrochlorides against Huh7 and T47D cell lines were reported in our previous study 13 . It is possible to find new chemical structures which can be drug candidates by the synthesis and investigation of the cytotoxic activities of semicyclic mono-Mannich bases having piperidine structure namely 3-aroyl-4-aryl-1-isopropylamino-4-piperidinols.…”

“…According to the studies carried out, the following activities of Mannich bases have been identified: anticancer 4 , cytotoxic [5][6][7][8][9][10][11][12][13] , anti-inflammatory [14][15][16] , anticonvulsant 17,18 and antifungal 19,20 . Their cytotoxic activities were attributed to the a,b-unsaturated ketone, which is available in the chemical structure of the compound or to the product produced by deamination process in vivo or under simulated conditions in vitro 7,21,22 .…”

“…Anti-tuberculosis 23 , anti-inflammatory 24 , H 3 antagonist 25 , sodium and calcium channel blocker 26 , anti-leukemia 27 , estrogen receptor modulator 28 , liver glycogen phosphorylase inhibitör 29 , map kinase inhibitor 30 and dopamine D 2 receptor antagonist 31,32 activities were reported in the literatures. Since Mannich bases were known with their remarkable cytotoxic activities in literature 4,13,33 , it could be useful to synthesize new chemicals having Mannich base structure for the solution of the problems mentioned above such as breast and liver cancers.…”