Doxorubicin-Based Hybrid Compounds as Potential Anticancer Agents: A Review

Abstract

The scarcity of novel and effective therapeutics for the treatment of cancer is a pressing and alarming issue that needs to be prioritized. The number of cancer cases and deaths are increasing at a rapid rate worldwide. Doxorubicin, an anticancer agent, is currently used to treat several types of cancer. It disrupts myriad processes such as histone eviction, ceramide overproduction, DNA-adduct formation, reactive oxygen species generation, Ca²⁺, and iron hemostasis regulation. However, its use is limited by factors such as drug resistance, toxicity, and congestive heart failure reported in some patients. The combination of doxorubicin with other chemotherapeutic agents has been reported as an effective treatment option for cancer with few side effects. Thus, the hybridization of doxorubicin and other chemotherapeutic drugs is regarded as a promising approach that can lead to effective anticancer agents. This review gives an update on hybrid compounds containing the scaffolds of doxorubicin and its derivatives with potent chemotherapeutic effects.

Keywords: cancer; chemotherapeutic drugs; doxorubicin; drug resistance; drug toxicity; hybrid compounds.

Figure 1

Chemical structure of doxorubicin (1).

Figure 2

Chemical structures of cholesteryl-doxorubicin compounds synthesized through amidation and esterification (2–5).

Figure 3

Chemical structures of doxorubicin-fatty acyl derivatives synthesized via the amino group (6a–i).

Figure 4

Chemical structures of the second generation of doxorubicin-fatty acyl derivatives synthesized via the hydroxyl group in position C-14 (7a–e).

Figure 5

Chemical structures of doxorubicin N-acyl hydrazones derivatives (8–9).

Figure 6

Chemical structures of doxorubicin-PA-α-LA derivatives conjugated via amide bond and hydrazone bond formation (10a–d).

Figure 7

Chemical structures of doxorubicin conjugated with DHA and α-LA conjugated through amidation and esterification (11a–d).

Figure 8

Chemical structure of doxorubicin-6-maleimidocaproyl hydrazone hybrid (12).

Figure 9

Chemical structures of doxorubicin-antioxidant derivatives synthesized via esterification (13a-b).

Figure 10

Chemical structure of quercetin-doxorubicin derivative synthesized via the amino group (14).

Figure 11

Chemical structures of formamidino-doxorubicin derivatives synthesized via the amino group (15a–e).

Figure 12

Chemical structure of dexamethasone-doxorubicin derivative synthesized via the amino group (16).

Figure 13

Chemical structure of doxorubicin modified by saccharides (17a–b).

Figure 14

Chemical structures of the second generation of doxorubicin modified by saccharides (18a–e).

Figure 15

Chemical structure of doxorubicin combined with combretastatin A4 via the amino group (19).

Figure 16

Chemical structure of steroidal anti-estrogen−doxorubicin bioconjugate (20).