Date of Award

2021

Document Type

Dissertation

Degree Name

Philosophy (Ph.D)

Department

Pharmaceutical Sciences

First Advisor

Vijaya Korlipara

Second Advisor

Xingguo Cheng

Third Advisor

John Wurpel

Abstract

A series of twenty-two quinazolinamine derivatives showing potent inhibitory activities on BCRP and P-gp was synthesized. The reversal study showed that when combined with the potent dual BCRP and P-gp inhibitors 7-8, 29-31, and 34, the IC50 value of mitoxantrone was decreased from 6.50 µM to the range of 0.24 - 0.35 µM for BCRP, and IC50 value of colchicine was decreased from 7.34 μM to the range of 0.12 - 0.29 µM for P-gp. Cyclopropyl quinazolinamine 29 (VKCY-1), which was a dual BCRP and P-gp inhibitor, and azide quinazolinamine 40 (VKCY-2), which was a BCRP inhibitor, were selected for mechanistic studies. The results revealed that target compound 29 (VKCY-1) changed the localization of BCRP in H460/MX20 cells and P-gp in KB-C2 cells rather than altering the expression level of BCRP or P-gp proteins, thus inhibiting the efflux of the anticancer drugs, which is different from the mechanisms of other reported ABC transporter inhibitors. Azide quinazolinamine 40 (VKCY-2), on the other hand, did not change the expression level or the localization of BCRP protein. In addition, compounds 29 (VKCY-1) and 40 (VKCY-2) significantly stimulated the ATP hydrolysis of BCRP transporter indicating that they can be competitive substrates of BCRP transporter, and thereby significantly increasing the accumulation of mitoxantrone in BCRP-overexpressing H460/MX20 cells. Azide quinazolinamine 40 (VKCY-2) with photoaffinity label can be a valuable probe for investigating the interactions of quinazolinamine derivatives with BCRP. After activation by the UV light, azide quinazolinamine 40 (VKCY-2) showed greater inhibitory effect on BCRP. Overall, this study indicated that quinazolinamine analogues can significantly reverse both BCRP- and P-gp-mediated MDR by blocking the efflux of anticancer drugs. Target compounds have the potential to be useful as BCRP and P-gp modulators to overcome MDR. The target quinazolinamine derivatives 7-8, 29-32, and 34 exhibited potency similar to that of the known BCRP inhibitor, Ko143. In addition, the P-gp inhibitory activities of quinazolinamine derivatives 7-8, 29-31, and 34 were greater than that of verapamil. Notably, the selected dual BCRP and P-gp inhibitors 7-8, 29-31, 34, and 40 showed improved metabolic stability than the standard pharmacologic tool Ko143.

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