AKR1C3 Inhibitory Potency of Naturally-occurring Amaryllidaceae Alkaloids of Different Structural Types

Hulcová, Daniela; Breiterová, Kateřina; Zemanová, Lucie; Siatkac, Tomás; Šafratová, Marcela; Vaněčková, Nina; Hošt'fálková, Anna; Wsól, Vladimı́r; Cahlíková, Lucie

doi:10.1177/1934578x1701200226

“…Bicolorine (9) also fully inhibited (100 %) the migration of PC-3 cells in a wound healing evaluation compared to norismine (21) (38.1 %), highlighting its significance in the tumor invasion and metastasis aspects of cancer biology [16]. However, none of the minor alkaloids subsequently examined for AKR1C3 activity, including galanthamine (1), belladine (6), and tetrahydromasonine (82), were able to register inhibitory activities of > 10 % relative to indomethacin (98 % inhibition) [12]. Montanine (13) (▶ Fig.…”

Section: Mechanistic Insightmentioning

confidence: 99%

“…Due to their more limited distribution and diversity, all other alkaloids found in these plants represent the minor alkaloid groups [9]. These include the galanthamine and phenanthridone groups as well as others, namely the belladine (6), ismine (7), trisphaeridine (8), bicolorine (9), cherylline (10), tazettine (11), homolycorine (12), montanine (13), lycosinine (such as lycosinine B 14), augustamine (15) and cripowellin (such as cripowellin A 16) groups [9]. While much has been detailed about the cytotoxic effects of the major alkaloid groups of the Amaryllidaceae [8], except for its phenanthridones, comparatively little is understood about such properties for the minor alkaloid groups.…”

Section: Introductionmentioning

confidence: 99%

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2021

Planta Med

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Over 600 alkaloids have to date been identified in the plant family Amaryllidaceae. These have been arranged into as many as 15 different groups based on their characteristic structural features. The vast majority of studies on the biological properties of Amaryllidaceae alkaloids have probed their anticancer potential. While most efforts have focused on the major alkaloid groups, the volume and diversity afforded by the minor alkaloid groups have promoted their usefulness as targets for cancer cell line screening purposes. This survey is an in-depth review of such activities described for around 90 representatives from 10 minor alkaloid groups of the Amaryllidaceae. These have been evaluated against over 60 cell lines categorized into 18 different types of cancer. The montanine and cripowellin groups were identified as the most potent, with some in the latter demonstrating low nanomolar level antiproliferative activities. Despite their challenging molecular architectures, the minor alkaloid groups have allowed for facile adjustments to be made to their structures, thereby altering the size, geometry, and electronics of the targets available for structure-activity relationship studies. Nevertheless, it was seen with a regular frequency that the parent alkaloids were better cytotoxic agents than the corresponding semisynthetic derivatives. There has also been significant interest in how the minor alkaloid groups manifest their effects in cancer cells. Among the various targets and pathways in which they were seen to mediate, their ability to induce apoptosis in cancer cells is most appealing.

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“…Bicolorine (9) also fully inhibited (100 %) the migration of PC-3 cells in a wound healing evaluation compared to norismine (21) (38.1 %), highlighting its significance in the tumor invasion and metastasis aspects of cancer biology [16]. However, none of the minor alkaloids subsequently examined for AKR1C3 activity, including galanthamine (1), belladine (6), and tetrahydromasonine (82), were able to register inhibitory activities of > 10 % relative to indomethacin (98 % inhibition) [12]. Montanine (13) (▶ Fig.…”

Section: Mechanistic Insightmentioning

confidence: 99%

“…This group of alkaloids, such as lycosinine B (14), are by definition 7-arylindoline entities [9]. In terms of Amaryllidaceae alkaloid chemosystematics, they may be considered as truncated analogs of the more recognizable lycorine (4) and homolycorine (12) alkaloids of the family [9]. It can be seen that the conversion of lycosinine B ( 14) into a homolycorine compound is a straightforward operation involving B-ring lactonization to connect C-6 to C-1 via its carboxylate [9].…”

Section: The Lycosinine Groupmentioning

confidence: 99%

“…Due to their more limited distribution and diversity, all other alkaloids found in these plants represent the minor alkaloid groups [9]. These include the galanthamine and phenanthridone groups as well as others, namely the belladine (6), ismine (7), trisphaeridine (8), bicolorine (9), cherylline (10), tazettine (11), homolycorine (12), montanine (13), lycosinine (such as lycosinine B 14), augustamine (15) and cripowellin (such as cripowellin A 16) groups [9]. While much has been detailed about the cytotoxic effects of the major alkaloid groups of the Amaryllidaceae [8], except for its phenanthridones, comparatively little is understood about such properties for the minor alkaloid groups.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Cytotoxic Agents in the Minor Alkaloid Groups of the Amaryllidaceae

Nair

¹

,

Staden

²

2021

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Over 600 alkaloids have to date been identified in the plant family Amaryllidaceae. These have been arranged into as many as 15 different groups based on their characteristic structural features. The vast majority of studies on the biological properties of Amaryllidaceae alkaloids have probed their anticancer potential. While most efforts have focused on the major alkaloid groups, the volume and diversity afforded by the minor alkaloid groups have promoted their usefulness as targets for cancer cell line screening purposes. This survey is an in-depth review of such activities described for around 90 representatives from 10 minor alkaloid groups of the Amaryllidaceae. These have been evaluated against over 60 cell lines categorized into 18 different types of cancer. The montanine and cripowellin groups were identified as the most potent, with some in the latter demonstrating low nanomolar level antiproliferative activities. Despite their challenging molecular architectures, the minor alkaloid groups have allowed for facile adjustments to be made to their structures, thereby altering the size, geometry, and electronics of the targets available for structure-activity relationship studies. Nevertheless, it was seen with a regular frequency that the parent alkaloids were better cytotoxic agents than the corresponding semisynthetic derivatives. There has also been significant interest in how the minor alkaloid groups manifest their effects in cancer cells. Among the various targets and pathways in which they were seen to mediate, their ability to induce apoptosis in cancer cells is most appealing.

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Computational modeling studies reveal the origin of the binding preference of 3‐(3,4‐di hydroisoquinolin‐2(1H)‐ylsulfonyl)benzoic acids for AKR1C3 over its isoforms

Kong

¹

,

Xing

²

,

Wu

³

et al. 2022

Protein Science

4

0

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As a key regulator for hormone activity, human aldo‐keto reductase family 1 member C3 (AKR1C3) plays crucial roles in the occurrence of various hormone‐dependent or independent malignancies. It is a promising target for treating castration‐resistant prostate cancer (CRPC). However, the development of AKR1C3 specific inhibitors remains challenging due to the high sequence similarity to its isoform AKR1C2. Here, we performed a combined in silico study to illuminate the inhibitory preference of 3‐(3,4‐dihydroisoquinolin‐2(1H)‐ylsulfonyl)benzoic acids for AKR1C3 over AKR1C2, of which compound 38 can achieve up to 5000‐fold anti‐AKR1C3 selectivity. Our umbrella sampling (US) simulations together with end‐point binding free energy calculation MM/GBSA uncover that the high inhibition selectivity originates from the different binding modes, namely “Inward” and “Outward,” of this compound series in AKR1C3 and AKR1C2, respectively. In AKR1C3/38, the tetrahydroquinoline moiety of 38 is accommodated inside the SP1 pocket and interacts favorably with surrounding residues, while, in AKR1C2/38, the SP1 pocket is too small to hold the bulky tetrahydroquinoline group that instead moves out of the pocket with 38 transitioning from an “Inward” to an “Outward” state. Further 3D‐QSAR and energy decomposition analyses suggest that SP1 in AKR1C3 prefers to bind with a rigid bicyclic moiety and the modification of the R3 group has important implication for the compound's activity. This work is the first attempt to elucidate the selectivity mechanism of inhibitors toward AKR1C3 at the atomic level, which is anticipated to propel the development of next‐generation AKR1C3 inhibitors with enhanced efficacy and reduced “off‐target” effect for CRPC therapy.

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AKR1C3 Inhibitory Potency of Naturally-occurring Amaryllidaceae Alkaloids of Different Structural Types

Cited by 9 publications

References 19 publications

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Cytotoxic Agents in the Minor Alkaloid Groups of the Amaryllidaceae

Computational modeling studies reveal the origin of the binding preference of 3‐(3,4‐di hydroisoquinolin‐2(1H)‐ylsulfonyl)benzoic acids for AKR1C3 over its isoforms

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