Synthesis and Biological Investigation of Bile Acid-Paclitaxel Hybrids

Abstract

Chenodeoxycholic acid and ursodeoxycholic acid (CDCA and UDCA, respectively) have been conjugated with paclitaxel (PTX) anticancer drugs through a high-yield condensation reaction. Bile acid-PTX hybrids (BA-PTX) have been investigated for their pro-apoptotic activity towards a selection of cancer cell lines as well as healthy fibroblast cells. Chenodeoxycholic-PTX hybrid (CDC-PTX) displayed cytotoxicity and cytoselectivity similar to PTX, whereas ursodeoxycholic-PTX hybrid (UDC-PTX) displayed some anticancer activity only towards HCT116 colon carcinoma cells. Pacific Blue (PB) conjugated derivatives of CDC-PTX and UDC-PTX (CDC-PTX-PB and UDC-PTX-PB, respectively) were also prepared via a multistep synthesis for evaluating their ability to enter tumor cells. CDC-PTX-PB and UDC-PTX-PB flow cytometry clearly showed that both CDCA and UDCA conjugation to PTX improved its incoming into HCT116 cells, allowing the derivatives to enter the cells up to 99.9%, respect to 35% in the case of PTX. Mean fluorescence intensity analysis of cell populations treated with CDC-PTX-PB and UDC-PTX-PB also suggested that CDC-PTX-PB could have a greater ability to pass the plasmatic membrane than UDC-PTX-PB. Both hybrids showed significant lower toxicity with respect to PTX on the NIH-3T3 cell line.

Mode of Actions of Bile Acids in Avoidance of Colorectal Cancer Development; and their Therapeutic Applications in Cancers - A Narrative Review

“…Fourthly Melloni et al [17], illustrated that CDC-PTX along with UDC-PTX in combination with paclitaxel, an anti cancer agent led to apoptosis induction in leukaemia HL60 cells along with NB4 acute promyelocytic leukaemia cells via a high output condensation reaction of CDCA along with UDCA (Figure 3E). Additionally, it was illustrated that CDC-PTX along with UDC-PTX RKO led to apoptosis induction in HCT-116 colonic carcinoma cells.…”

“…Additionally, various laboratories have generated innovative Bile Acid obtained substance for evaluation of the tumor suppressive actions of bile acids. These substances were illustrated to result in induction of programmed cell death (PCD) in different cancer cells besides possess tumor repressive action [14][15][16][17][18][19][20][21][22][23][24]. Cell death possesses a key part in embryonic formation, sustenance of homeostasis, as well as elimination of injured cells.…”

Mechanism of Bile Acid-Induced Programmed Cell Death and Drug Discovery against Cancer: A Review

“…Fourth, Melloni et al [25] showed that CDC-PTX and UDC-PTX combined with paclitaxel (PTX), an anticancer drug, induced apoptosis in HL60 and NB4 acute promyelocytic leukemia cells through a high-yield condensation reaction of CDCA and UDCA (Figure 3E). It was also shown that CDC-PTX and UDC-PTX RKO induced apoptosis in HCT-116 colon cancer cells.…”

“…In addition, several laboratories have synthesized novel bile acid derivatives to explore the tumor-suppressive function of bile acids. These derivatives were shown to induce programmed cell death in several cancer cells, and have tumor-suppressive effects [22][23][24][25][26][27][28][29][30][31][32].…”

A Novel Docetaxel-Biotin Chemical Conjugate for Prostate Cancer Treatment

“…Since cancer cell proliferation and apoptosis are regulated by cellular signals, the inhibition of these signals is helpful for eliminating cancer [35]. It is worth adding that some other conjugated taxanes were reported recently, such as two novel conjugated derivatives of Chenodeoxycholic acid-Paclitaxel and Ursodeoxycholic acid-Paclitaxel that displayed similar or lesser anticancer activity compared to Paclitaxel [36], and Docetaxel-Palmitate-conjugated derivative [37] that offered a decreased IC50 compared to that of Docetaxel. IDD-1010 at a low concentration (10 nM) inhibited cell proliferation and arrested proliferating PC3-Luc cells in vitro at the G1-phase.…”