Natural Products Chemistry & Research

Aspochalasins, a Structurally Diverse Fungal Derived Bioactive Sub-group of Cytochalasans and Their Activities

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Abstract

Aspochalasins are a structurally diverse subgroup of cytochalasans produced by fungal secondary metabolism. While much is still unknown about their precise mechanisms of action, they appear to elicit cytostatic and cytotoxic effects similarly as their parental group. Those effects include antibacterial, anti-tumoral, phytotoxic, anti-proliferative, and anti-viral activities. Their potencies are often as varying as their structures with minor modifications on their frequently substituted macrocyclic scaffold causing complete loss or significant enhancement of activity. Due to their various biomedically relevant effects and a large number of macrocyclic carbons with tolerance for diverse functional group substitutions, aspochalasins appear to be good candidates for structural optimization which may produce compounds with potent and targeted effects. This article aims to categorize the underline features of this subgroup of naturally produced compounds.

Introduction

Cytochalasans are a large class of fungal secondary metabolites with varying anti-tumoral, anti-microbial, and other biological activities [1]. Since their first discovery in 1967, the size of this class has steadily grown and is now made up of at least 300 compounds [2], which are characterized by a highly substituted isoindole ring fused to a larger often 11 or 12 membered macrocyclic ring (Figure 1).

Figure 1: Representative planar structures of aspochalasin Z (1) with a 11-membered macrocyclic ring and aspochalasin J (2) with a 12-membered macrocyclic ring. Isoindole unit is drawn in blue and macrocycle in green.

Cytochalasans with a 2-methylpropyl substitution at C-3 of the isoindole unit are sub-grouped as aspochalasins (Figure 1). By 2004 only 12 such compounds containing this substitution had been identified [3]. As of April 2021, this number has swelled to greater than 100; the associated online Supporting Information provides a compilation of names, structures and sources of those natural products, and thus serves as a reference for compounds whose structures are not presented in this article. A majority of aspochalasins have been isolated as white or pale-yellow amorphous powder from Aspergillus species; however, they have also been found to be produced by other fungal species such as Phoma, Periconia, Spicaria, Trichoderma or Westerdykella [4- 18]. This small but rapidly expanding group of fungal natural products have demonstrated proclivity for vast structural diversity and varying biological activities. This article aims to categorize the underline features of aspochalasins.

Structural Diversity and Categorization

While aspochalasins are easily characterized and recognizable by their C-3 2-methylpropyl group, the macrocycle affords the most opportunity for structural novelty via addition of functional groups or attachment of large complex molecules on the C-17, -18, -19, and/or -20 positions.

Commonly, aspochalasins are described based upon their overall ring structure. The most common ring arrangement is the tricyclic 5/6/11 organization as seen in aspochalasin Z 1; (Figure 1); however, other ring arrangements such as 5/6/12 as seen in aspochalasin J 2; (Figure 1), or 5/6/6/7, 5/6/9, 5/6/7 have also been identified.

In addition to the previously mentioned ring structural categorization, aspochalasins can also be classified as ketone aspochalasins for having a key C-21 ketone or ester aspochalasins for having a C-21 ester on the macrocycle fused to C-9 of the isoindole ring (Figure 1), or as open-ring aspochalasins for lack of a macrocyclic ring. The exceptions to this rule are a hydroxyl group seen on C-21 of aspochalazine A attributable to its iconic azabicyclo moiety [19], a replacement of the ester ketone with NH in flavichalasine O [20], and periconiasins D-F due to their severely truncated macrocycles [9].

Ketone Aspochalasins

Roughly 2 of every 3 (80/117) aspochalasins identified to date contain what can be considered the basic form of the macrocycle with a C-21 ketone moiety (Figure 2). 1 is thought to be the “basic version” of all aspochalasins with the emblematic C-5, -6, and -14 methyl groups but no further modifications to the macrocycle or the isoindole ring [21].

Figure 2: Representative planar structures of the ketone subgroup of aspochalasins.

Though this group contains the most common and basic 5/6/11 ring structure, it nonetheless encompasses interesting compounds such as iizukine C (3) with a unique 1,2,4-triazole group attached to C-19 [22], in addition to the more familiar compounds such as aspochalasins C-E (4-6) with hydroxyl groups at the frequently substituted C-17, -18, and/or -19 positions (Figure 3) [23]. Spicarins A-B (7-8) have four acetyloxy groups attached to C-17 and their macrocycle-fused isobenzofuran ring [11]. Tricochalasin A (9) markedly contains a heavily modified 5/6/6 tricyclic ring attached to C-18, -19, and -20 [24].

Figure 3: Occurrences of functional attachment to C-7, -14, -16, -17, -18, -19, and -20 of aspochalasins as well as their structural categorization (*) based upon the carbon connecting the macrocycle to the isoindole ring. With few exceptions, aspochalasins typically have a methyl group attached at C-14 and an unsubstituted C-16. For C-17, -18, -19, -21 and -21, substitutions are often oxygenated functional groups or larger high MW modifications.

Despite the presumed availability of C-13 and C-15 on the macrocycle for functional group substitutions, there is no example of substitution on those atoms other than internal ring closure as seen in flavichalasines C-E (10-12), trichalasin H (13), aspergillin PZ (14), 16-hydroxymethylaspergillin PZ (15), and trichoderone B (16). Ring closure often generates an epoxy moiety fused to the macrocyclic ring [16-18,25,26].

Apart from C-13 and C-15, the next most uncommonly substituted atom in the macrocycle is C-16 (Figure 3). Phomacin C (17) [4,6] and several naturally occurring analogs of 17 have been isolated and found to have an atypical hydroxymethyl attachment at C-16 including bioactive 17 diastereomer 19,20-dihydrophomacin C (18) [5]. Among these analogs, several were also determined to have an equally rare methoxy group. While methoxy has not yet been observed at C-17, it is seen at C-18 in aspochalasin K (19) [3]. Methoxy has also been seen at C-19 of trichalasin G (22) [16], which is an analog of aspochalasin I (20) [3] and flavichalasine F (21) [25]. Finally, a methoxy group is present at C-20 in flavichalasine L (23) [25].

Complex ring systems expand far past the relatively simple tricyclic, tetracyclic, and pentacyclic structures yielding compounds such as the cage-like hendecacyclic epicochalasines A-B, which are thought to be generated from the fusion of an epicoccine dimer to 5 [27] similar to asperflavipines A-B, which are characterized by their tetradecacylic and nonacyclic structures, respectively [2]. Epicoccine is likewise integrated into the structure of asperchalasines A-H which theoretically arise from aspochalasins B and P (24-25) and aspergilasines A-D from 5 [28-31].

Multifarious ring structures are not the only characteristics which give aspochalasins their rich diversity; many identified aspochalasins have interesting groups attached to their macrocycle rather than complex interconnections. Aspochalamins A-D is notable for tripeptide sequences attached to the macrocycle of 1 or 5 and were only found in stationary culture [21,32].

Within the ketone aspochalasin group are other oddities such as bisaspochalasin A wherein a 5 monomer is homodimerically linked at C-17, -18, and -19 to the cleaved macrocycle of another [33]. In the same way, bisaspochalasins B and C are homodimerized 24 but are instead linked by a peculiar thioether bridge and differentiated by bisaspochalasin C’s equally odd C-7 peroxy seen only one other time in trichalasin E [16,33]. While sulfur is rarer than carbon, nitrogen and oxygen in microbial natural products methylthio containing aspochalasins V and W [34] as well as modified cysteine containing cyschalasins A and B [35] have been described. Periconiasin H rounds out the sulfur-containing aspochalasins, however, its sulfoxide group is not its most striking structural feature. The periconiasins are much smaller than typical aspochalasins with ring structures as small as 5/6/7 seen in periconiasin G [8]. Periconiasins D-F are technically not ester nor ketone aspochalasins due to a C-15/18 ring closure on their truncated macrocycle [7,9]. Regardless, the periconiasins still retain the other key aspochalasin characteristics such as the C-3 2-methylpropyl group and isoindole subunit [7-9]. The last common modification is addition of a hydroxyl group to C-7 of the isoindole ring, as seen in 16, aspochalasins L, U and W [36,37], and trichalasin C [15]. This group of compounds represent the lone non-macrocyclic aspochalasin modifications thus far documented (Figure 3).

Ester Aspochalasins

Ester aspochalasins have their macrocycle connected to the isoindole unit by what is now known to be a Baeyer-Villiger generated C-21 ester [38,39] and are largely 5/6/12 structured compounds, though unsurprisingly this is not the only possible ring structure (Figure 4). Aspochalasin F (26) was the first documented occurrence of a C-21 ester aspochalasin reported in 1997 [40]. This group is no less diverse than the ketone aspochalasins and often contains compounds which share structural similarity with analogous ketone counterparts. For example, the uncommon 17, 18 epoxy group found in C-21- ketone aspochalasin G is also seen in the ester-containing 26 [40]. Likewise, many ester aspochalasins are also present with hydroxyl or carbonyl groups attached to C-17, -18, and/or -19 (Figure 3) [3,22,25,38,41] with internal ring structures such as those seen in amiaspochalasins B and C (27-28) [38].

Figure 4: Representative planar structures of the ester subgroup of aspochalasins.

Exceedingly unique amiaspochalasin A (29) has a methyl group affixed to C-16 rather than the largely ubiquitous 14-methyl placement seen in nearly all of its aspochalasin congeners (Figure 3) [38]. Similar absence of 14-methyl is only seen in periconiasin F and flavichalasine A [25] which both contain 14-methylene making 29 the only recognized C-14 unsubstituted aspochalasin. Similar C-16 methylation is seen in 16α-methylaspochalasin J (30) [18] and phomacin A [41] which both, however, retain 14-methyl; interestingly, none of these 16-methyl bearing compounds were isolated from Aspergillus sp.

Open-ring Aspochalas

Opening of the macrocycle rather than a ring closure is the source of the last major category of aspochalasins (Figure 5) [42]. The products of those ring breakages have been from both ketone and ester aspochalasins and can occur at many locations on the macrocycle. For example, amiaspochalasin F and G (31-32) [38] are thought to be generated by cleavage of the C-21 ester group from their immediate precursors. Similar ring opening is seen in amiaspochalasin I [42], secochalasins A and B (33-34) [35], and a monomer of the strangely cross-linked bisaspochalasin A [33]. Overall, the open-ring aspochalasins are a small and rare subset of aspochalasins (Figure 3).

Figure 5: Representative planar structures of the open-ring subgroup of aspochalasins.

Whether those are true terminal secondary metabolites, shunt intermediates during biosynthesis or simply breakdown products from the isolation process is unknown as they have not been reported to have meaningful bioactivities.

Biosynthesis Of Aspochalasins

While the biosynthesis of aspochalasins is not as thoroughly documented as cytochalasans, limited studies demonstrate that their formation is similar to the parental cytochalasan class which arises from hybrid polyketide synthase–nonribosomal peptide synthase (PKS–NRPS) biosynthetic pathways [43,44]. As aspochalasins are solely distinguished from cytochalasans by their characteristic C-3 2-methylpropyl group, it was postulated that their origins are due to incorporation of leucine in the nascent structure rather than tryptophan, phenylalanine, tyrosine, valine, or alanine [24,43] which gives rise to other well-known cytochalasan subgroups such as the chaetoglobosins, pyrichalasins, and alachalasins [35,43].

Specifically, a 36,705-bp biosynthetic gene cluster, ffs, was identified in marine-derived A. flavipes CNL-338 that yields many aspochalasins including 4, 6, 14, 21, aspochalasin M, TMC-169, and flavichalasine G [44]. The ffsA PKS module iteratively incorporates malonyl-CoA building blocks followed by addition of L-leucine by an NRPS module [45].

Similarly, a PKS-NRPS gene cluster phm was upregulated by overexpression of transcriptional regulatory gene phmR in Parastagonospora nodorum, which resulted in the production of a previously characterized phomacin derivative [5] that was renamed phomacin D (35) and phomacins E-F 36-37; (Figure 6) [46]. Further, when phmA and phmE were expressed in A. nidulans, prephomacin (38) was produced. While 38 is not a conventional aspochalasin, it was proposed that this compound is the precursor to 35, which can logically be derived following enolization and a Diels-Alder addition [46].

Figure 6: Planar structures of phomacins D-F and prephomacin. 37 notably has a C-20 acetonyl group [46], which is similarly seen in aspochalasins N and O [13]. Whether this functional group is naturally occurring is unclear; though they appear to be an artifact of using acetone during extraction processes [13,46]. Experiments to verify this theory have emphasized the reactivity of C-20 [46].

Synthetically generating those often complex molecules from their biologic precursors complements the ability to understand their biosynthetic origin. This has proven to be an achievable endeavour even in the intricate asperchalasine structures [28,29] to aid in understanding their ability to selectively inhibit cell cycling [47].

The proposed biosynthetic pathway for the unique sulfurcontaining aspochalasins involves a 1,4-addition of cysteine to intermediate 24 followed by either a deamination-methylation or acylation decarboxylation step to arrive at the structure of cyschalasins A and B, respectively [35]. A similar biosynthetic strategy is proposed for the sulfur-containing bisaspochalasins B and C wherein cysteine is also postulated to conduct a nucleophilic addition to the unsaturated C-20 of 24 [33].

The complexly linked epicochalasines A and B are suggested to be formed through a Diels-Alder reaction of 5 and two epicoccine molecules followed by (3+2) cycloaddition and a subsequent nucleophilic addition step to yield epicochalasines A or B depending on the original orientation of epicoccine at the time of cycloaddition [27]. A similar biogenetic pathway is proposed for the creation of aspergilasine A which undergoes an intramolecular (3+2) cycloaddition to arrive at its final structure [31].

Biological Activities

As indicated by the Greek root meaning ‘cell relaxation’ [48], cytochalasans are known to elicit anti-proliferative activity through targeting and capping the actin cytoskeleton [49]. This actin capping affects normal cell processes such as cell adhesion, motility, signalling, and cytokinesis [1,35]. Though the biological activity of cytochalasans is well documented, aspochalasins have sporadically reported data (Table 1) which obfuscates our ability to determine their importance, structure-activity relationship, and any specific mechanisms of action which vary from current understanding of cytochalasan activity. For example, cytochalasans have been shown to elicit cytotoxic as well as cytostatic effects, which would presumably allow for the use of the cytostatic compounds in cancer therapy despite their lack of cytotoxicity [43]; whether aspochalasins operate similarly is not extensively studied. Importantly, there is a need for some levels of modification on the macrocycle to cause cytotoxicity as the aspochalasin ‘basic version’, 1, has no documented bioactivities [21].

35-36 inhibited actin polymerization and 37 did not. These findings suggest that aspochalasins block actin polymerization similar to cytochalasans but these activities are not present in the erroneously generated 37. Further supporting the suggestion of actin inhibition as a mechanism of action, 35-36 both exerted antigerminative phytotoxicity with 35 selectively [50] preventing germination of only monocot Avena sativum and not dicots Arabidopsis thaliana or Lepidium sativum [46].

To date, the most potent aspochalasin reported is TMC-169, a rather simple C-18-hydroxyl analog to 1. Despite or possibly due to its simplicity, it has shown remarkable cytotoxicity [51] against U937, Jurkat, HL-60, WiDr [52], and HCT-116 (IC50: 0.81, 0.2, 0.68, 0.83, 0.78 μg/ml, respectively) [53]. Another minimally substituted compound, 5, caused cell death in dexamethasone inducible ras-dependent Ba/F3-V12 cells (IC50: 1.9 μg/ml), PC3 cells (IC50: 11.14 μg/ml), and exhibits moderate antimicrobial effects against Gram-positive microorganisms [50].

That is not to say that simplicity is a requirement for activity in aspochalasins. Complex compounds such as the tripeptide-linked aspochalamins elicited moderate growth inhibition zones against Gram-positive microorganisms at 1 mg/ml and aspochalamins A-C had GI50 less than 10 μg/ml against HM02, MCF7, HepG2, and Huh7 cancer cells [21]. Though it was cytotoxic to NCI-H460, MCF-7, and SF-268 [3], 20 interestingly demonstrated no cytotoxic effect on Mel-Ab cells at <100 μM; however, 20 inhibited the ability of Mel-Ab to carry out melanogenesis (IC50: 22.4 μM) by blocking tyrosinase activity [51].

Common to many aspochalasins is having a C-17 hydroxyl or C-18 hydroxyl moiety (Figure 2). There is evidence to support the claim that hydroxyl at C-18 on the macrocycle can be necessary for antibacterial activity. The C-18 hydroxyl of aspochalamin C [21,32] was necessary for its activity against Arthrobacter globiformis when compared to the hydroxyl-lacking aspochalamin D. Similar activity against A. globiformis is seen in 5 which also bears a C-18 hydroxyl. Interestingly, 5 exerted antibiotic activity against many Gram-positive species which were not inhibited by aspochalamins A-D, indicating that their C-19 tripeptide linkage had a negative effect on their antibiotic potencies [21].

When compared for antibiotic activity, 5, 14, and 20 all caused growth inhibition against S. epidermidis and S. aureus; however, this inhibition is greatly diminished in 14 and 20 (MIC: 20 μM vs. 10 μM) [21,41]. Neither 14 nor 20 are inhibitory to E. coli or B. cereus whereas 5 (MIC: 10 μM) is. 24 was not inhibitory to any of these organisms (MIC: >20 μM) [41]. Given their structural similarities, it is clear that antibacterial potency among simple 17,18-diol compounds is greater in the C-21 ketone variant and this activity is not enhanced by changing C-17 hydroxyl to C-17 carbonyl or C-17 epoxy. Likewise, the C-17,18-diol-19,20-epoxy bearing aspochalasin H, demonstrated no antibiotic activity against these targets [41]. Aspochalasin H also did not prompt cytotoxicity against Ba/F3 cells whereas 5 had high potency (IC50: 0.49 μg/ml) against the same target [54], indicating that this observed C-17 hydroxyl preference may carry over to anticancer effects as well.

While there was little difference in the anticancer activity between 26 and aspochalasin G against HL-60 and MH-60, there was a substantial difference in inhibition zones when 30 μg of either was added to cultures of Gram-positive and Gram-negative species. 26 was inactive whereas aspochalasin G was inhibitory to B. subtilis, S. aureus, M. luteus, A. laidlawii, P. oryzae, and L-form bacteria [40]. Given this, it appears that there is a role for C-21 ketone in antibiotic activity.

As for the effects of internal epoxides, 13-15 have shown anticancer and antimicrobial effects [17,18,26]. Other uncommon compounds such as the 1,2,4-triazole-carrying 3 and the sulfurcontaining cyschalasins also have documented cytotoxicity against cancer cells [22,35].

On the isoindole ring, aspochalasins with C-7 hydroxyl also exhibit important biological activities. Aspochalasin U has shown moderate dose-dependent anti-TNFα activity in L929 cells which led to increased cell survivability by blocking necrotic cell death [36]. Aspochalasin L, which similarly contains C-7 hydroxyl, has shown to inhibit the HIV-1 integrase activity but not HIV replication in HuT78 T-cells (IC50: 71.7 μM) [37].

22 is a C-7-H structural analog to aspochalasin L. Whether 22 has similar anti-HIV integrase activity is unknown. Further study of the comparative effects of these two compounds would aid in determining the importance or lack thereof for the uncommon yet often active C-7 hydroxyl aspochalasins. No activity was observed in C-7 hydroxyl, C-20 methylthio-containing aspochalasin V whereas its C-7 unsubstituted analog aspochalasin W was active against PC3 (IC50: 30.4 μM) and HCT-116 (IC50: 39.2 μM) [34]. Further SAR is possible here due to the number of identified aspochalasins with hydroxyl or methoxy groups (Figure 3).

The number of hydroxyl groups on the macrocycle is not necessarily indicative of the degree to which a compound will be cytotoxic. For example, amiaspochalasins D-E both have C-18 hydroxyl but amiaspochalasin D also has a C-17 hydroxyl. Despite being more substituted, amiaspochalasin D was significantly less cytotoxic to HL60, A549, Hep3B, U87, and SW480 than its structural analog [38].

Investigation of the role of C-16 methyl moiety is possible through comparison of 2 and 30. Though they have not been tested against the same targets, both compounds have shown moderate cytotoxicity [3,18]. Amiaspochalasin A lacked activity against a panel of cancer cell lines [38]. This deficiency in activity may have more to do with the absence of the extremely pervasive C-14 methyl rather than the presence of C-16 methyl.

Further, phomacin A demonstrated potent toxicity against HT-29 cells (IC50: 0.6 μg/mL) but the toxicity is reduced in C-16 methoxy carrying phomacin B (IC50: 1.4 μg/mL) or its C-21 ketone analogue 17 (IC50: 7.4 μg/mL) [6]. Of a group of six 17 analogs which have been described, none demonstrated cytotoxicity (IC50: >50 μM) against HT-29 except for 18 (IC50: 49.09 μM) [5].

Interestingly, the size of aspochalasins does not appear to be determinative of their activities. Compounds as small as a MW of 359.5 and as large as a MW of 976.2 have been found to be biologically active [7,33]. The smallest active aspochalasins, periconiasins A-B, both showed sub-micromolar potency against HCT-8 (IC50: A: 0.9, B: 0.8 μM). Though they differed only by the orientation of their C-17 hydroxyl moiety, they had dissimilar potency against BGC-823 (IC50: A: 2.1, B: 5.1 μM) and periconiasin B was the only compound of the two to be cytotoxic to Bel-7402 (IC50: 9.4 μM) [7]. The largest aspochalasin discovered to date, asperchalasine A, which consists of two 24 monomers attached to a central epicoccine has exhibited ability to selectively arrest the cell cycle at G1 through inhibition of cyclin A, CDK2, and CDK6 in cancerous cells [47]. Other epicoccinecarrying aspochalasins, epicochalasins A-B and asperflavipine A, have shown cancer cell cytotoxicity through the activation of caspase-3 and degradation of PARP [2,27], a process similarly noted in flavichalasine F [25] (Figure 7).

Figure 7: Proposed plausible relationships and biosynthetic derivations of various ketone aspochalasins from the ‘basic’ aspochalasin Z to more complexly substituted molecules. Compounds highlighted in green have documented biological activity; those not highlighted have no documented biological activity though are not necessarily inactive. Numbers in bracket are reference numbers.

Conclusion

Much is now known about the vastness of aspochalasin chemical space, though little is currently known about their structureactivity relationships which dictate their prolific anticancer, antimicrobial, phytotoxic and anti-viral profiles. As the size of the aspochalasin subgroup has now eclipsed 100 compounds, there is a necessity as well as an opportunity to delve deeper into their structure-activity relationships.

Investigation of the responsible biosynthetic gene clusters may be helpful to discover more cryptic aspochalasins or further understand their biogenesis. Though their structures are often complex, many of these secondary metabolites have analogous compounds which differ by only one functional moiety. Because of this and considering their documented potential to elicit a wide array of biomedically relevant effects, the next sensible step is to methodically analyse the structure-activity relationships against common targets or to attempt synthetic structural optimization particularly on the macrocycle which has shown to permit attachment of substitutions that could potentially increase potency or targeting specificity. Given their well-documented de novo syntheses and reactive macrocyclic ring, aspochalasins may be appropriate scaffolds for further drug development as it is clear that size does not necessarily preclude aspochalasins from eliciting meaningful activity, though there is some bias for smaller molecules.

Among the potential modifications to the macrocycle, C-14 methyl as well as C-17 and/or C-18 oxygenated functional groups appear to be preferred for bioactivity. 4, 5, and 24 appear to be functional ‘starting blocks’ for building a large portion of this set of compounds and would thus be ideal candidates for any optimization attempts as their syntheses have been well documented.

Most importantly, the precise mechanism of action of those compounds is still largely unknown. While their ability to cause cytotoxic or cytostatic activity is not disputed and there are suggestions that aspochalasins operate through actin capping, determining whether there are any other mechanistic activities which cause this wide range of intracellular effects is crucial to creating strategies to optimize their structures.

Conflict of Interest

There is no conflict of interest to be reported by any of the authors.

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