Yong-Mei Cui

Molecular mechanism of pharmacological activation of BK channels

Large-conductance voltage- and Ca2+-activated K+ (Slo1 BK) channels serve numerous cellular functions, and their dysregulation is implicated in various diseases. Drugs activating BK channels therefore bear substantial therapeutic potential, but their deployment has been hindered in part because the mode of action remains obscure. Here we provide mechanistic insight into how the dehydroabietic acid derivative Cym04 activates BK channels. As a representative of NS1619-like BK openers, Cym04 reversibly left-shifts the half-activation voltage of Slo1 BK channels. Using an established allosteric BK gating model, the Cym04 effect can be simulated by a shift of the voltage sensor and the ion conduction gate equilibria toward the activated and open state, respectively. BK activation by Cym04 occurs in a splice variant-specific manner; it does not occur in such Slo1 BK channels using an alternative neuronal exon 9, which codes for the linker connecting the transmembrane segment S6 and the cytosolic RCK1 domain—the S6/RCK linker. In addition, Cym04 does not affect Slo1 BK channels with a two-residue deletion within this linker. Mutagenesis and model-based gating analysis revealed that BK openers, such as Cym04 and NS1619 but not mallotoxin, activate BK channels by functionally interacting with the S6/RCK linker, mimicking site-specific shortening of this purported passive spring, which transmits force from the cytosolic gating ring structure to open the channels gate.

Design, synthesis, and characterization of BK channel openers based on oximation of abietane diterpene derivatives

Oxime ether derivatives at the benzylic position of unsubstituted, dichloro, trichloro, and monobromo derivatives of the aromatic C-ring of dehydroabietic acid and podocarpic acid were synthesized and evaluated as BK channel openers in an assay system of CHO-K1 cells expressing hBKα channels. Detailed SAR analysis showed that the oximation was particularly effective in the cases of dehydroabietic acid derivatives, and some of these oxime derivatives showed more potent BK channel activities than the standard compound, NS1619. The present studies provide a new structural basis for development of efficient BK channel openers.

Novel BK channel openers containing dehydroabietic acid skeleton: structure-activity relationship for peripheral substituents on ring C.

A series of dehydroabietic acid (DHAA, 2) derivatives was synthesized and evaluated as BK channel openers in an assay system of CHO-K1 cells expressing hBKalpha channels. Systematic modifications of the peripheral functionality of ring C of DHAA showed that the introduction of a nitro or (thio)urea group in ring C greatly enhanced the BK channel-opening activity.

Novel oxime and oxime ether derivatives of 12,14-dichlorodehydroabietic acid : Design, synthesis, and BK channel-opening activity

Oxime ether derivatives of the benzylic ketone of 12,14-dichlorodehydroabietic acid (diCl-DHAA, 4b) were synthesised, and their BK channel-opening activity was evaluated in an assay system of CHO-K1 cells expressing hBKalpha channels. Oxime ether structure on the B ring of diCl-DHAA significantly increased the BK channel-opening activity.

Design, synthesis and characterization of podocarpate derivatives as openers of BK channels.

We found that the podocarpic acid structure provides a new scaffold for chemical modulators of large-conductance calcium-activated K(+) channels (BK channels). Structure-activity analysis indicates the importance of both the arrangement (i.e., location and orientation) of the carboxylic acid functionality of ring A and the hydrophobic region of ring C for expression of BK channel-opening activity.

The synthesis and BK channel-opening activity of N-acylaminoalkyloxime derivatives of dehydroabietic acid.

A series of N-acylaminoalkyloxime derivatives of dehydroabietic acid were synthesized and evaluated for BK channel-opening activities in an assay system of CHO-K1 cells expressing hBKα channels. The structure-activity relationship study revealed that a non-covalent interaction between the S atom of the 2-thiophene and the carbonyl O atom may contribute to conformation restriction for interaction with the ion channel. This research could guide the design and synthesis of novel abietane-based BK channel opener.

The synthesis and antistaphylococcal activity of dehydroabietic acid derivatives: Modifications at C-12

A series of 12-oxime and O-oxime ether derivatives of dehydroabietic acid were synthesized and investigated for the antibacterial activity against Staphylococcus aureus Newman strain and five multidrug-resistant strains (NRS-1, NRS-70, NRS-100, NRS-108, and NRS-271). The aromatic oximate derivative 11a showed the highest activity with MIC of 0.39-0.78μg/mL against S. aureus Newman. Of note, compounds 10b, 11 and 14 showed the most potent antibacterial activity against five multidrug-resistant S. aureus with MIC values of 1.25-3.13μg/mL. These results offered useful information for further strategic optimization in search of the antibacterial candidates against infection of multidrug-resistant Gram-positive bacteria.

Improved laboratory synthesis of YC-071, a potent azole antifungal agent

An improved laboratory synthesis of YC-071, a potent azole antifungal agent, has been developed. Compared with the original route, the new route is operationally simple, requiring only limited purification of all the intermediates. The new route is an important scalable synthesis, which meets the need for YC-071 for use in preclinical studies.

Design, synthesis, and structure-activity relationship studies of novel tetrazole antifungal agents with potent activity, broad antifungal spectrum and high selectivity

In this letter, we report our efforts to design, synthesize and evaluate biological activities of a series of novel hybridized compounds containing 1-tetrazole and 4-pyridinyl-1,2,4-triazole-3-one. An analysis of structure-activity data indicates that the target compounds with bulky and hydrophobic side chains exhibited stronger activities against the Candida spp and Cryptococcus neoformans tested than those of fluconazole and racemic VT-1161. Furthermore, 13k and 13ad were active against Microsporum gypseum, which was resistant to racemic VT-1161. In addition, 13k, 13ac and 13ad, with good in vitro activities against all of pathogenic fungi tested except for Aspergillus fumigatus, had no inhibition of human CYP3A4, suggesting a low risk of drug-drug interactions.