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The pharmacological activities of C19-diterpenoid alkaloids are related to their basic skeletons (e.g., aconitine-type or lycoctonine-type). Also, few studies have been reported on the chemosensitizing effects of diterpenoid alkaloids. Consequently, this study was aimed at determining the chemosensitizing effects of synthetic derivatives of lycoctonine-type C19-diterpenoid alkaloids on a P-glycoprotein (P-gp)-overexpressing multidrug-resistant (MDR) cancer cell line KB-VIN. The acyl-derivatives of delpheline and delcosine showed moderate cytotoxicity against chemosensitive cancer cell lines. Among non-cytotoxic synthetic analogs (1−14), several derivatives effectively and significantly sensitized MDR cells by interfering with the drug transport function of P-gp to three anticancer drugs, vincristine, paclitaxel, and doxorubicin. The chemosensitizing effect of derivatives 2, 4, and 6 on KB-VIN cells against vincristine were more potent than 5 μM verapamil, and derivatives 4 and 13 were more effective than 5 μM verapamil for paclitaxel. Among them, 2 in particular increased the sensitivity of KB-VIN cells to vincristine by 253-fold. [ABSTRACT FROM AUTHOR]

Diterpenoid alkaloids, the main components of plants of the genera Aconitum, Delphinium, and Garrya, are a group of natural products with notable chemical properties and biological activities. Several C19-diterpenoid alkaloid components from Delphinium elatum cv. Pacific Giant, as well as their derivatives, exhibited cytotoxic activity against lung, prostate, cervical, and vincristine-resistant cervical cancer cell lines. In the current phytochemical investigation on the seeds of D. elatum cv. Pacific Giant, eleven new C19-diterpenoid alkaloids, elapaciline (1), meladine (2), melapacitine (3), iminoeladine (4), 19-oxopaciline (5), 19-oxopacinine (6), N-deethyldelpheline (7), N-deethylpacinine (8), N-deethyl-19-oxoeladine (9), N-deethyl-N-formyleladine (10), and N-deethyl-N-formyldelpheline (11), together with 15 known C19-diterpenoid alkaloids were isolated. Their structures were elucidated by extensive spectroscopic methods including NMR (1D and 2D), IR, and MS (HRMS). Three known diterpenoid alkaloids, 6-dehydrodelcorine (12), delelatine (23), and 6-dehydroeldelidine (24), were isolated for the first time from this plant. Six of the new C19-diterpenoid alkaloids (2, 4–7, and 11) and three of the known diterpenoid alkaloids (18, 23, and 24) were evaluated for cytotoxic activity against five human tumor cell lines. [ABSTRACT FROM AUTHOR]

Although many diterpenoid alkaloids have been evaluated recently for antiproliferative activity against human cancer cell lines, little data have been offered relating to the antiproliferative effects of hetisine-type C 20 -diterpenoid alkaloids, such as kobusine ( 1 ), likewise as their derivatives. A total of 43 novel diterpenoid alkaloid derivatives ( 2-10 , 2b , 3a , 3b , 6a-16a , 7b , 9b , 10b , 13 , 15-26 , 15b , 18a , 23a , 27a ) were prepared by C-11 and -15 esterification of 1 . Antiproliferative effects of the natural parent compound ( 1 ) and all synthesized kobusine derivatives against human cancer cell lines, including a triple-negative breast cancer (TNBC) cell line as well as a P-glycoprotein overexpressing multidrug-resistant subline, were assessed. The structure-based design strategy resulted in the lead derivative 11,15-dibenzoylkobusine ( 3 ; average IC 50 7.3 μM). Several newly synthesized kobusine derivatives (particularly, 5-8 , 10 , 13 , 15-26 ) exhibited substantial suppressive effects against all tested human cancer cell lines. In contrast, kobusine ( 1 ), 11,15-O-diacetylkobusine ( 2 ), 11-acylkobusine derivatives ( 3a , 6a , 9a , 11a , 12a , 15a , 27a ), and 15-acylkobusine derivatives ( 2b , 3b , 7b , 9b , 10b , 15b ) showed no effect. The most active kobusine derivatives primarily had two specific substitution patterns, C-11,15 and C-11. Notably, 11,15-diacylkobusine derivatives ( 3 , 6-10 , 13 , 15 , 16 , 18 , 23 ) were more potent compared with 11- and 15-acylkobusine derivatives ( 3a , 3b , 6a-10a , 7b , 9b , 10b , 13a , 15a , 15b , 16a , 18a , 23a ). Derivatives 13 and 25 induced MDA-MB-231 cells to the sub-G1 phase within 12 h. 11,15-Diacylation of kobusine ( 1 ) appears to be crucial for inducing antiproliferative activity in this alkaloid class and could introduce a new avenue to overcome TNBC using natural product derivatives., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)