Limonin as a Starting Point for the Construction of Compounds with High Scaffold Diversity

Article abstract of DOI:10.1002/anie.202104228

Structurally complex natural products have been a fruitful source for the discovery and development of new drugs. In an effort to construct a compound collection populated by architecturally complex members with unique scaffolds, we have used the natural

Full text of DOI:10.1002/anie.202104228

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Accepted Article
Title: Limonin as a Starting Point for the Construction of Compounds
with High Scaffold Diversity
Authors: Lucia Furiassi, Emily Tonogai, and Paul J. Hergenrother
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10.1002/anie.202104228
Angewandte Chemie International Edition
RESEARCH ARTICLE
Limonin as a starting point for the construction of compounds
with high scaffold diversity
Lucia Furiassi, Emily J. Tonogai, and Paul J. Hergenrother*
L. Furiassi, E. J. Tonogai, Prof. P. J. Hergenrother
Department of Chemistry
Carl R. Woese Institute for Genomic Biology
Cancer Center at Illinois
University of Illinois at Urbana-Champaign
Urbana, IL 61801 (USA)
E-mail: hergenro@illinois.edu
Supporting information for this article is given via a link at the end of the document.
Abstract: Structurally complex natural products have been a fruitful have been thoroughly scoured for biologically active
source for the discovery and development of new drugs. In an effort constituents.[14]
to construct a compound collection populated by architecturally
Scaffold diversity is a feature of compound collections that
complex members with unique scaffolds, we have used the natural can have an impact on the success of biological screening.[15] In
product limonin as a starting point. Limonin is an abundant addition to providing compounds of different shapes and
triterpenoid natural product and, through alteration of its heptacyclic flexibilities, the scaffold (defined as the minimum core framework
core ring system using short synthetic sequences, a collection of 98 of a given compound)[16] also places peripheral functional groups
compounds was created, including multiple members with novel ring in various positions of three-dimensional space, facilitating
systems. The reactions leveraged in the construction of these
differential interaction with biological targets.[17] As such,
compounds include novel ring cleavage, rearrangements, and compound collections composed of members that are complex
cyclizations, and this work is highlighted by the discovery of a novel and include members with scaffold diversity would be welcome.
B-ring cleavage reaction, a unique B/C-ring rearrangement, an
Natural products are a source of inspiration in drug
atypical D-ring cyclization, among others. Computational analysis discovery with unsurpassed biological activity and scaffold
shows that 52 different scaffolds/ring systems were produced during diversity. Over 66% of all small-molecule approved drugs
the course of this work, of which 36 are unprecedented. Phenotypic between 1981 and 2019 trace their structural origins back to
screening and structure−activity relationships identified compounds natural products.[18] Natural products are typically characterized
with activity against a panel of cancer cell lines.
by complex scaffolds with considerable three-dimensionality, a
high number of stereogenic centers and a high fraction of sp3–
hybridized carbons (Fsp3),[3] and such parameters have been
associated with improved target selectivity and successful
Introduction
19-20]
progression through clinical trials.[4,
However, given the
significant challenges with the isolation and purification of novel
natural products, they are usually under-represented in screening
collections.
High-throughput screening (HTS) is a cornerstone of drug
discovery, routinely used to identify lead compounds that become
first-in-class drugs.[1-2] As such, the type of drugs entering the
market in part reflects the composition of screening libraries.
Most compound collections are biased by medicinal chemistry
conventions, such as Lipinski’s rule of five for oral bioavailability,[3]
and thus are largely populated by relatively planar molecules, with
functional groups arrayed around a small number of common
skeletons.[4-5] The vast majority of such compounds would be
considered structurally simple relative to natural products, and as
screening these collections has increased and as the identified
leads have progressed forward to approval, the resulting drugs
tend to also have a low number of stereogenic centers and a low
percentage of sp3-hybridized carbons.[6-7] Such collections have
been outstanding for the discovery of biologically active
compounds for targets with binding sites that favor flat molecules
(e.g., kinase inhibitors), but less valuable in providing hits for other
types of targets (e.g., transcription factors[8-9] and protein-protein
interactions[10-11]) and complex multifactorial disorders (e.g.,
antibiotic-resistant bacteria).[12-13] Another drawback associated
with the use of commercially available libraries in screening
experiments is that such widely distributed collections are likely to
To fill this gap, several creative strategies have been
developed to rapidly generate complex compounds, including
construction of natural product-inspired scaffolds,[21-25] diversity-
oriented synthesis (DOS)[26-29] and biology-oriented synthesis
(BIOS).[30-32]
Inspired by nature, we have reported a
complementary strategy named Complexity-to-Diversity (CtD).
The CtD approach takes advantage of the structural complexity
inherent within readily available natural products to generate
unique complex compounds through ring distortion reactions (i.e.,
ring expansion, contraction, cleavage, fusion, and
rearrangement).[33-34] This method has been applied to several
natural products, including adrenosterone,[35] gibberellic acid,[35]
quinine,[35] abietic acid,[36-37] sinomenine,[38] lycorine,[39]
pleuromutilin,[40-42]
ilimaquinone[45] and steroids such as dutasteride and abiraterone
acetate[46]
The resulting collections of natural product-like
yohimbine,[43]
haemanthamine,[44]
.
compounds have been instrumental in developing predictive
guidelines for small molecule accumulation in E.coli,[47] and led to
G protein-coupled receptor antagonists,[48] a new class of
antiplasmodial agents,[49] and the discovery of a novel and potent
inducer of ferroptotic cell death.[42]
1
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RESEARCH ARTICLE
Nature offers a multitude of natural products that are
exceptional starting points for the CtD strategy. The limonoids
are a valuable source of biologically active natural products.[50]
Although more than 300 limonoids have been isolated to date,
their occurrence in the plant kingdom is confined mainly to the
order Rutales, which includes the families Meliaceae and
Rutaceae.[51] Limonin (1, Scheme 1) was the first member of this
structural class to be identified, isolated from citrus fruit in 1841.[52]
Limonin is a highly oxygenated modified triterpenoid with a dense
interlocking ring system, consisting of seven rings (including the
epoxide ring) and nine stereogenic centers, and it is characterized
by a high Fsp3 (0.73) and an unusually high number of
heterocycles (lean ring index, LRI = 2.5, defined as the number of
heterocycles divided by the number of carbocycles in a given
compound). Limonin, other limonoids, and their metabolites have
demonstrated a broad range of biological activities in mammalian
systems,
including
anticancer,[53]
antibacterial,[54]
With the objective of
anti-
inflammatory,[55-56] and antiviral.[57]
constructing a variety of complex compounds with novel ring
systems/scaffolds in a limited number of steps, herein we apply
the CtD strategy to limonin (1), generating a compound collection
with numerous complex and differentially decorated molecular
frameworks; the pathways to key compounds 2-20 are
overviewed in Scheme 1. As an initial evaluation, all compounds
were tested for their ability to induce death of cancer cells in
culture, but numerous other applications of this and analogous
compound collections can be envisioned.
Scheme 1. Overview of the scaffolds generated from the triterpenoid limonin.
2
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Results
Diversifying desoxylimonin
Further skeleton manipulations of the A’ and B rings starting
from desoxylimonin (2) are shown in Scheme 3. The synthesis
of 10 was reported by Geissman and Tulagin in 1946, by refluxing
2 with red phosphorus.[64] To avoid the use of this toxic reagent,
Design of compound collection
The limonin heptacyclic skeleton and functional group
composition provide outstanding starting points for the
development of novel and complex compounds, as overviewed in
Scheme 1, and highlighted by the generation of multiple unique
core ring systems/scaffolds. In designing synthetic routes to
complex compounds from limonin, several known transformations
were first leveraged to convert 1 into previously synthesized citrus
limonoids 2-4 (Scheme S1) and the ring cleavage analogs 5 and
a
more practical protocol utilizing hydrobromic acid was
developed and optimized (see Scheme S3 for proposed
mechanism). Under these conditions 10 and a small quantity of
its C17-epimer (22) were isolated. The spirocyclic compound 10,
whose structure was confirmed by X-ray crystallography, was
further altered using AlCl3-catalyzed electrophilic aromatic
substitution (using conditions previously developed on limonin)[65]
to obtain a small series of novel acylated derivatives (23-25).
Based on the success of Beckmann rearrangement carried
out on 1 (in Scheme 2), a B-ring expansion of the spirocycle 10
was envisioned. Thus, 10 was converted to the corresponding
oxime (S7, Scheme S4) and subsequently treated with cyanuric
S1 (Scheme S1).[58-61]
During the construction of new
compounds, several unprecedented reactions were discovered to
alter the overall ring systems, including cleavage reactions of the
B-ring, rearrangement of the B/C-ring system, and opening and
novel cyclization of the D-ring. The ketone on the B-ring of 1
provides a suitable handle to generate scaffold diversity through
ring expansion (6-7) and subsequent ring cleavage reactions (8-
9). A’- and B-ring cleaved versions of 2 (10-11) can be further
exploited to achieve both skeletal and functional group diversity
(12-13). The B-ring-alcohol of limonol (3) and the carboxylic acid
of limonolic acid (4) were leveraged to generate unknown ring
systems via ring rearrangement (14-16), transformation (17), and
cleavage (18). Finally, ring manipulations via D-ring contraction
(19-20) were devised using 5 as a starting point.
chloride generating lactam 12 with
a regioselective NH
incorporation between the carbonyl and the olefin. Although both
S7 formation and Beckman rearrangement occur with low yields
(25 and 8% respectively), these transformations enabled the
generation of a novel molecular skeleton. The different migratory
aptitudes observed in Beckmann rearrangement products of 6
and 12 rely on the different configurations assumed by the
hydroxyl group of the two corresponding oximes (Z and E
respectively). Sodium borohydride reduction of the B-ring ketone
of 10 yielded β-alcohol 26 as a single diastereoisomer, further
converted into the acylated derivatives 27-29 by reacting with the
suitable acyl chloride in dichloromethane and pyridine (Scheme
3).
Treatment of 2 with sodium hydroxide at high temperature
gave an unusual B-ring cleavage reaction, forming carboxylic acid
11 in quantitative yield. Compound 11 is a known limonin
metabolite and natural product, first isolated from Pseudomonas
in 1974 [66], but to our knowledge, it has never been synthesized
before this work. The course of the reaction, which requires the
Diversifying limonin through B-ring expansion and E-ring
opening
The B-ring of limonin presents the opportunity for the
construction of new compounds with unexplored ring systems
through ring expansions (Scheme 2). Seven-membered rings
are medicinally important molecular frameworks commonly found
in diverse bioactive natural products, but they are under-
represented in compound screening collections and marketed
drugs due to their challenging syntheses.[62] Attempts to generate
the seven-member ring derivative 6 via a Schmidt reaction
resulted in compound degradation. However, the known E-oxime
intermediate (S2, Schemes S1 and S2) was synthesized[58] and
utilized as the substrate for a Beckmann rearrangement using
cyanuric chloride, yielding lactam 6 as a single constitutional
isomer. Under these conditions, only the selective migration of
the most substituted anti-group was observed. Baeyer-Villiger
oxidation of 1 resulted in the analogous ring expanded lactone 7.
Further modifications of 6 and 7 were realized by subjecting
the two compounds to limonin A-ring cleavage conditions
(Scheme 2).[61] The reaction carried out on lactam 6 follows the
classical limonin reactivity,[61] with the A-ring opening to derivative
8. However, the same conditions applied to 7 lead to selective
cleavage of the newly expanded B-ring (9).
presence of
a δ-ketone α,β-unsaturated lactone, can be
envisioned by hydroxyl anion attack on the ketone carbonyl and
Many naturally occurring citrus limonoids contain a furan
ring attached to the D-ring, designated as the E-ring. To generate
a compound with alterations in the E-ring, 1 was subjected to
ozone-mediated oxidative cleavage. While furans are known to
generate carboxylic acid derivative via ozonolysis,[63] oxidation of
the furan ring of 1 with ozone gives rise to novel dihydroxy ketone
21 (Scheme 2). The synthesis of this highly oxygenated product
likely occurs by the formation of an α-ketoacid intermediate that
converts to the dihydroxy analog 21.
Scheme 2. Limonin B-ring expansion, E-ring opening, and further
manipulations of the A and B rings.
3
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10.1002/anie.202104228
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Scheme 3. Synthesis and functionalization of the ring-opened derivatives 10 and 11.
subsequent ring cleavage of the C7-C8 bond and olefin
migrations (refer to Scheme S5 for proposed mechanism).
Compound 11 afforded the opportunity to generate a small set of
B-ring cleaved analogs via amide coupling reactions (30-33), and
a subsequent copper-catalyzed azide-alkyne reaction to form
triazole 13 (Schemes 3 and S6).
transformation (17, Scheme 4). After the displacement of the
secondary alcohol by a chlorine ion, A-ring lactone conversion to
a 5,6-dichloro-3,4-dihydro-2H-pyran ring occurs.
Novel ring rearrangements of limonol
Carbocation rearrangements are common reactions
employed by both nature and synthetic chemists to generate
complex molecules with new scaffolds.[67-68] Thus, we envisioned
using the C7-alcohol of limonol (3) to trigger a skeleton
rearrangement through carbocations, hydride shift, and alkyl shift,
as shown in Schemes 4 and S7. Indeed, treatment of 3 with
hydroiodic acid led to an unexpected ring system, compound 14.
This ring rearrangement likely occurs through the displacement of
C7-hydroxyl by iodine, which after C11-hydride abstraction
initiates a rearrangement cascade culminating in the formation of
compound 14 (refer to Scheme S8 for proposed mechanism).
The fused ring systems within complex terpenoids are
poised
for
manipulation
through
Wagner-Meerwein
rearrangement, yielding complex and structurally divergent
scaffolds.[69-70] Therefore, we sought to apply classical Wagner-
Meerwein skeletal rearrangement to 3. Treatment of 3 with triflic
anhydride provides activated alcohol 34, which can undergo a
1,2-shift to generate 15 as a single diastereoisomer (Scheme 4).
After the C7 carbonium ion formation, the 1,2-sigmatropic shift of
the methyl group could readily occur suprafacially with retention
of configuration. The absolute configuration of 15 was confirmed
by X-ray crystallography (Scheme 4).
By extending the reaction time, structural elaboration occurs
via epoxide ring-opening and elimination to form 16 and 35 in low
yields. Interestingly, in situ activations of the hydroxy function of
3, using phosphorus pentachloride, disfavors the Wagner-
Meerwein rearrangement, and triggers a new unexpected ring A
4
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10.1002/anie.202104228
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RESEARCH ARTICLE
Scheme 4. Rearrangement of the B and C rings of limonol (3).
Scheme 5. Manipulation of the ring-rearranged derivative 4.
This unprecedented reaction allowed the generation of an
unusual 5,6-dichloro-3,4-dihydro-2H-pyran moiety in one step.
The formation of 17 likely occurs by phosphorus pentachloride-
mediated A-lactone activation, followed by chloride ion addition to
the ipso carbon of the lactone carbonyl. The formed intermediate
form the tertiary carbocation, which triggers the carboxylic acid
attack to C13 and subsequent suprafacial methyl 18 migration
(refer to Scheme S13 for proposed mechanism). Notably,
increasing the acid concentration generates the dichlorinated
derivatives 43 and 44 via tetrahydrofuran ring-opening, as
previously observed by treating ethers with strong acids (see
Scheme S14 for proposed mechanism).[74] The stereoselective
nature of the novel D-ring cyclization was further confirmed by X-
ray crystallography of the C20 (S)-diastereoisomer 43 (Scheme
6). Oxidation of 43 and 44 with Dess-Martin periodinane (DMP)
generated the two diastereomeric ketones 20 (also confirmed by
X-ray) and 45. Lastly, intermediate 5 was decarboxylated to
generate aldehyde 46.
can then further undergo an elimination reaction and
a
subsequent second chloride ion incorporation at the alpha carbon
(see Scheme S9 for the proposed mechanism).
Limonilic acid-based ring distortion strategy
Limonilic acid (4) served as a key substrate to construct a
subset of compounds with the rearranged A and B ring systems
(Scheme 5). Coupling of the carboxylic acid of 4 with suitable
amines provided amide derivatives (36-37). Compound 37 was
modified using the azide-alkyne cycloaddition to build a small set
of ring fusion analogs (38-41).
The versatility of the novel ring B cleavage reaction
discovered in the construction of 11 (in Scheme 3) was further
demonstrated through the application of the developed conditions
to the ring systems of 4 and 36 (Scheme 5). The suitable δ-
ketone α,β-unsaturated lactone starting points S22 and S20 were
generated from 4 and 36 via epoxide treatment with hydroiodic
acid (Schemes S10 and S11). Compounds S22 and S20 were
then submitted to sodium hydroxide ring cleavage yielding the
new scaffolds 42 and 18.
Ring D-distortion strategy
Finally, compound 5 also served as a starting point to build
new scaffolds, as shown in Schemes 6 and S12. Key to this
diversification strategy was the use of brønsted acids, which have
had a broad utility in natural product chemistry.[71-73] Treatment of
5 with hydrochloric acid in dioxane at high temperature leads to
two simultaneous transformations: the cleavage of the A’ ring (in
a similar manner observed for compound 10 in Scheme 3) and
an atypical D ring cyclization, forming compound 19 (Scheme 6).
This heretofore-unknown ring cyclization occurs in
a
stereoselective fashion. The mechanistic underpinnings of this
transformation are envisioned to proceed by epoxide opening to
5
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Scheme 6. Manipulation of the D-ring cleaved derivative 5.
6
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RESEARCH ARTICLE
Figure 1. Scaffold collection derived from limonin (1).
7
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RESEARCH ARTICLE
Computational analysis of limonin-derived complex
molecules
the set of 99 compounds, 52 unique Murcko scaffolds were
identified (Figure 1 and Table S2). Among these, 16 are known
(present in existing natural products or synthesized derivatives)
while 36 are novel. Based on the Murcko fragments, structural
features and molecular diversity was evaluated by the generation
of a library scaffold tree (Figures S17-S27). In addition, a
Tanimoto coefficient matrix (a measure of the similarity of different
fingerprints) was also generated for all compounds (Figure S28),
further highlighting the balance between scaffold diversity and
compound density of the synthesized limonin collection.
Herein, the limonin scaffold was utilized to construct a collection
of 98 complex compounds (compounds 2-47 and S1-S52 in
Figures S1 and S2); 15 of these were previously known in the
literature, while 83 are new compounds. Besides the 46
compounds described here, the synthetic route to the other 52
compounds are available in the Supporting Information
(Schemes S15-S19). All compounds were isolated at >95%
purity, and >20 mg quantities were produced for most compounds
(including many of those produced through low-yielding routes,
such as 14 and 17, Table S1). All the new CtD compounds
accessed from limonin were submitted to chemoinformatic
complexity analyses and compared to the physiochemical
properties of existing screening libraries, natural products, and
approved drugs (Figures S3-S16). The set of 99 compounds
(including limonin) shows an average of Fsp3 = 0.66, average
number of stereogenic centers = 7.77, ring fusion density = 0.27,
and ring complexity index = 1.30, values markedly higher
compared to those of standard screening collections (see
Figures S3-S16).
Scaffold diversity was also assessed for these compounds
generated from limonin. Several computational methods have
been developed to analyze scaffold diversity, including the
derivation of Murcko scaffold (defined as the union of ring systems
and linkers in a given compound)[75] and the scaffold tree
methodology (which describes the ring systems arranged in a
hierarchical tree by removing rings one by one according to a set
of prioritization rules).[76] By removing all the appendages from
Assessment of limonin CtD collection against cancer cells in
culture
Molecular scaffolds play a pivotal role in the navigation of
biologically relevant chemical space, thus we hypothesized that
the variety of molecular frameworks generated herein from
limonin could enhance the likelihood of identifying new bioactive
agents relative to traditional screening collections.
Phenotypic screening is
a powerful strategy for the
identification of bioactive molecules capable of modulating
complex diseases.[77] The wide utility of this screening approach
relies on its ability to identify new bioactive compounds before full
elucidation of targets or mechanisms of action. With the objective
of identifying new anticancer compounds and new chemical
scaffolds with anticancer activity, all the synthesized compounds
were assessed for their ability to kill cancer cell lines in culture,
with initial screening using the ES-2 (ovarian carcinoma) and
HCT116 (colorectal carcinoma) cell lines (Figure S29).
Cell Line
23
25
47
48
HCT116
ES-2
3.28 ± 0.65
3.65 ± 0.39
7.62 ± 1.85
3.88 ± 0.08
5.53 ± 0.22
1.71 ± 0.90
8.45 ± 1.56
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>50 [b]
>100
1.60 ± 0.44
0.58 ± 0.03
2.59 ± 0.21
1.61 ± 0.08
0.64 ± 0.01
0.78 ± 0.01
7.10 ± 1.70
A549
HOS
MDA-MB-231
A172
Hep-G2
Figure 2. Biological evaluation of key compounds against cancer cells in culture. Bioactivity is expressed as a 72-hour IC50 value (in M) against a panel of cell
lines, as measured by Alamar Blue assay. Data represent mean ± SEM, Raptinal (50 μM) was used as dead control, n = 3 biological replicates; [a] number of steps
from limonin, [b] not soluble at 100 M.
8
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RESEARCH ARTICLE
Cell viability was assessed after 72 hours treatment with
compounds at 20 µM. From these assessments, compound 23
emerged as a promising anticancer agent, inducing over 85% cell
death (at 20 µM) against both cancer cell lines, and was thus
further evaluated against a panel of cancer cell lines with a full
concentration range such that dose-response curves could be
generated and half-maximal inhibitory concentrations (IC50s)
values calculated. As shown in Figure 2, compound 23 has broad
activity across cell lines from different cancer types with an IC50
range of 1.7–8.4 µΜ and near 100% Emax (maximum achievable
effect,[78] see dose-response curves in Supporting Information
Figure S30). One feature of 23 is the presence of an electrophilic
group on the furan. α-chlorocarbonyl electrophiles are reactive
with nucleophilic substrates such as cysteine thiols but can exhibit
surprisingly low off-target reactivity and minimal activity towards
glutathione, and thus can be suitable warheads for covalent
drugs.[79] The α-chloroketone of 23 was systematically modified,
revealing its importance to anticancer activity; for example,
acylated compound 25 is inactive, and other electrophiles at this
position also result in a significant drop in anticancer activity
(Figure S31). The presence of the electrophilic warhead is not
sufficient for anticancer activity, however, as compounds carrying
the α-chlorocarbonyl electrophiles on the same position of the
furan ring, but with different chemical skeletons, did not show any
activity (47 and S39). Structure-activity relationship (SAR)
studies also revealed that inversion of configuration at the furan
(S57) results in loss of potency and that other functional groups
(B-ring ketone and A-ring unsaturation, compounds S59, S67,
S69 and S60, S64) could be removed without diminishment of
activity (for full SAR refer to Supporting Information Figures S31-
S35, and Schemes S20 and S21). Importantly, propargyl
compound 48 retains excellent activity against cancer cells in
culture, even more potent than 23 (Figures 2 and S36), setting
the stage for future target identification efforts. Additional data
suggest that compounds 23 and 48 induce death in cancer cells
via apoptosis (Figures S37 and S38), and these compounds do
not induce lysis of red blood cells (Figure S39).
converted into the natural product sinoracutine in only five
steps[38] (compared to the twelve steps required for its total
synthesis).[81] We anticipate that the compounds disclosed herein,
and others generated from different natural products, will find
utility in a wide variety of biological investigations.
Data availability
The X-ray crystallography data have been deposited in the
Cambridge Crystallographic Data Centre (CCDC) using the
following identifiers (www. ccdc.cam.ac.uk/structures/): 2082412
(compound 3), 2082413 (compound 10), 2082419 (compound 15),
2082414 (compound 20), 2082415 (compound 26), 2082416
(compound 44), 2082417 (compound S36) and 2082418
(compound S42).
Acknowledgements
We are grateful to the University of Illinois and the NIH
(R01GM118575) for funding this work. We thank T. Woods and
D. Gray (UIUC) for collection and analysis of X-ray data and F.
Nocera (UIUC) for assistance in chemoinformatic analysis.
Keywords: limonin • scaffold diversity • ring distortion •
natural products • anticancer
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19-34.
Ring distortion of the heptacyclic scaffold of limonin allowed
not only the generation of a variety of natural product-like
scaffolds (119 compounds, considering 98 CtD compounds and
21 SAR analogs) and the discovery of novel reactions (cleavage
of δ-ketone α,β-unsaturated lactone functional groups, unique
B/C-rings rearrangement triggered by hydroiodic acid,
unprecedented D-ring cyclization) but also afforded the
opportunity for facile synthesis of a natural product. Indeed,
nature takes advantage of divergent pathways from a common
intermediate to generate multiple different natural products. This
“natural products from natural products” result can also be a
fortuitous consequence of applying new transformations to
natural products, seen herein in the construction of compound 11
from limonin, and observed previously with sinomenine,
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10.1002/anie.202104228
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RESEARCH ARTICLE
Entry for the Table of Contents
Many compound collections used in high-throughput screening are composed of members whose structural complexity is considerably
lower than that of natural products. Here the natural product limonin was leveraged to generate 98 architecturally complex compounds
with significant scaffold diversity. Phenotypic screening of the collection led to the discovery of novel anticancer compounds.
11
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