Abstract
Cervical cancer is among the leading causes of death in women. Chemotherapy options available for cervical cancer include highly cytotoxic drugs such as taxol, cisplatin, 5-florouracil, and doxorubicin, which are not specific. In the current study, we have identified a new peptide conjugate (Fur4-2-Nal3-Ala2-Phe1-CONH2) (conjugate 4), from screening of a small library of tripeptide-conjugates of furan, as highly potent anticancer compound against human cervical cancer cells (HeLa cells) (IC50 = 0.15 ± 0.05 µg/mL or 0.28 +/− 0.09 µM). Peptides were constructed on Rink amide resin from C- to N-terminus followed by capping by α-furoic acid moiety. The synthesized peptides were purified by recycling RP-HPLC, and structures of all the peptides were confirmed by using FABMS/ESIMS, 1H- NMR, 13C-NMR, and HR-FABMS. Conjugate 4 was furthermore found to be specifically active against human cervical cancer cells since it did not inhibit the proliferation of other human normal cells (HUVEC (human umbilical vein endothelial cells) and IMR-90 (normal human fibroblasts)), and cancer cells tested (HUVEC, MCF-7, and MDA-MB-231 cells), as well as in mice 3T3 cells (normal fibroblasts). This study revealed a good structure activity relationship of various peptide conjugates. Conjugate 4 in branched forms (4a and 4b) were also synthesized and evaluated against HeLa cells, and results revealed that both were inactive. Atomic force microscopy (AFM) studies and staining with rhodamine 123 and propidium iodide (PI) revealed that conjugate 4 possesses a membranolytic effect and causes the loss of mitochondrial membrane potential.
Highlights
Cervical cancer is the fourth most common type of cancer among women [1]
Conjugate 4 was found to be inactive against human breast cancer cells (MCF-7 and MDA-MB-231 cells) and on normal cells (HUVEC, IMR-90, and 3T3 cells)
The structure activity relationship was established in the peptide library
Summary
Cervical cancer is the fourth most common type of cancer among women [1]. In lower- and middle-income communities (LMIC), it is second most common type of cancer among women, overall it is the third most common cancer after oral and breast cancer. Peptides identified from different natural sources have poor solubility, low bioavailability, and are sensitive to proteolytic enzymes [10,11,12] These limitations are overcome by introducing some changes to the skeleton of the peptide chain, such as the introduction of various unusual amino acids or conjugation with heterocyclic moieties. It has been reported that the conjugation of a biologically active heterocyclic moiety in peptide chains enhances the potency of the compounds by increasing cell permeability [9,15]. In view of the aforementioned, the current study was designed on the synthesis and anticancer screening of a furoyl moiety conjugated with a tripeptide sequence containing natural, unnatural, hydrophobic, and cationic amino acid residues, in order to develop novel conjugates with enhanced protease stability and to check their potential against human cervical cancer cells
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