Table 5.

Summary of mutual prodrugs of 5‐FU with improved biological activity.

Compd.	Type of hybrid	Linker	Study	Outcomes	Ref.
1 a,b	5‐FU/HDAC	carbamate	molecular docking, in vitro antiproliferative assay, in vitro HDAC inhibition, in vitro stability assay	↓ side effects	[42]
4 a–f, 5 6 a–f	5‐FU/deoxy‐ podophyllotoxin	amino acid, diamine	in vitro cytotoxicity assay, immunofluorescence, in vitro HUVECs tube formation assay	↑ antiproliferative activity	[50]
7 a–e	5‐FU/ubenimex	carbamate	in vitro antiproliferative assay, in vitro HUVECs tube formation assay, in vivo antitumor activity assay	Antiproliferative activity	[61b]
11 a–d, 12 a–d	5‐FU/oxaliplatin	succinyl, glutaryl	in vitro antiproliferative assay, measurement of water‐octanol partition coefficient, apoptosis analysis, stability in PBS/DMF buffer, in vivo antitumor activity	↑ antiproliferative activity ↓ side effects	[71]
13 a–e	5‐FU/ parthenolide	ester, triazole	in vitro cytotoxicity assay, cell apoptosis assay, western blot assay, nuclear morphology assay, drug accumulation assay	overcoming 5‐FU resistance	[79]
14 a–d, 15 a–d, 16 a,b, 17 a,b	5‐FU/ pentacyclic triterpenes	alkyl	in vitro cytotoxicity assay, intracellular Ca2+ generation, detection of intracellular ROS, Cell cycle assay, detection of caspase‐3/8	↑ antiproliferative activity	[85]
19	5‐FU/HO‐1 inhibitor	succinyl	in vitro cytotoxicity assay, measurement of HO‐1 and HO‐2 enzymatic activities, in vitro stability in acid, neutral, basic buffer solution and in porcine esterase solution, in silico prediction of physicochemical, ADME, and toxicity properties	comparable antiproliferative activity ↓ side effects	[95]