Chlorambucil-Bearing Hybrid Molecules in the Development of Potential Anticancer Agents

Abstract

Increasing cases of cancer have been a primary concern in recent decades. Developing new chemotherapeutics is challenging and has been faced with limitations, such as multidrug resistance, poor specificity, selectivity, and toxicity. The aforementioned factors contribute to treatment failure. Hybrid compounds have features that can overcome the limitations mentioned above. Chlorambucil, an anticancer drug that is used to treat prostate and breast cancer, suffers from poor aqueous solubility and specificity, a short half-life, and severe side effects, including anaemia and bone marrow suppression. It compromises the immune system, resulting in treatment failure. Hence, its combination with other pharmacophores has been reported to result in effective anticancer agents with fewer side effects and high therapeutic outcomes. Furthermore, this review gives an update (2010 to date) on the developments of chlorambucil hybrid compounds with anticancer activity, and the structure-activity relationship (SAR), and also highlights future strategies for developing novel anticancer agents.

Keywords: cancer; chlorambucil; drug resistance; hybridization; treatment.

Figure 1

Strategies used to design hybrid drugs.

Figure 2

Structure of Chlorambucil.

Figure 3

Chemical structure of Chlorambucil–estradiol hybrids substituted at the 16 α (1a–c) and 16 β positions (2) [31].

Figure 4

Chemical structures of the 1st generation of Chlorambucil–tyrosine hybrids (3–4) [32].

Figure 5

Chemical structures of the 2nd generation of Chlorambucil–tyrosine hybrids (5–10) [30].

Figure 6

Chemical structures of Chlorambucil–tyrosine hybrids synthesized by Pocasap et al. via esterification (11a) and amidation (11b) [33].

Figure 7

Chlorambucil–methionine Hybrid 12 [14].

Figure 8

Chemical structure of Chlorambucil–7α-testosterone hybrid 13 [34].

Figure 9

Chemical structure of Chlorambucil–platinum hybrid compound 14 [35].

Figure 10

Chemical structure of Chlorambucil–platinum hybrid compound 15 [37].

Figure 11

Chemical structures of platinum-based Chlorambucil hybrids with anticancer activity (16a,b) [38].

Figure 12

Chemical structures of platinum–Chlorambucil compounds 17a,b synthesized by Qin et al. [39].

Figure 13

Chemical structure of Chlorambucil incorporated with hydrocarbon and fluorocarbon derivatives, the * represents the position where the R will bond (18a–c) [40].

Figure 14

A novel therapeutic agent (19) chemical structure synthesized from Chlorambucil and asparagine moieties [42].

Figure 15

Chemical structures of Chlorambucil–lipid hybrids (20a–c) and modified lipids (20d and 20e) [43].

Figure 16

Chemical structures of Chlorambucil–DNA-HDAC inhibitors (21 and 22) [44,45].

Figure 17

Chemical structure of Chlorambucil–olaparib hybrid compounds 23a,b [46].

Figure 18

Chemical structure of mitochondrial–targeting Chlorambucil hybrids 24a–d [47].

Figure 19

Chlorambucil–honokiol hybrid chemical structure 25 [51].

Figure 20

Chemical structure of Chlorambucil–polyamide hybrid 26 synthesized by Funakoshi et al. [52].

Figure 21

Chemical structures of Chlorambucil–polyamide hybrids 27a–c synthesized by Hirose et al. [53].

Figure 22

Chemical structure of Chlorambucil–phenosafranin hybrid 28 [54].

Figure 23

Chemical structure of Chlorambucil–artemisinin hybrid 29–30 synthesized by Dai et al. [55].

Figure 24

Chemical structures of Chlorambucil–evodiamine hybrid drugs 31a–d synthesized by Hu et al. [60].

Figure 25

Chemical structure of Chlorambucil–brefeldin hybrids 32a–c synthesized by Han et al. [61].

Figure 26

Possible linkers to develop hybrid drugs.

Figure 27

Possible solutions to improve Chlorambucil’s efficacy.

Figure 28

Examples of nanocarriers.