8 th Semester report Submitted In Partial Fulfillment of the

Requirements For The Degree of Master of Science

Synthesis and In Silico Assessment of Spiro and

Oxa Spiro Oxindole Compounds: Exploring their
Anticancer Potential

Submitted by
AUROBINDO PATNAIK
Int. MSc 4 th year, NISER. Roll no- 2011040

Under the guidance of

Dr. NAGENDRA KUMAR SHARMA
Associate professor
School of Chemical Sciences
NISER, Bhubaneswar
 DECLARATION

I hereby declare that I am the sole author of this thesis in partial

fulfilment of the requirements for a postgraduate degree from National
Institute of Science Education and Research (NISER). I authorize NISER
to lend this thesis to other institutions or individuals for the purpose of
scholarly research.

Signature of the Student

Date:25/04/2024

This work reported in the thesis entitled “Synthesis and In Silico

Assessment of Spiro and Oxa Spiro Oxindole Compounds: Exploring
their Anticancer Potential” was carried out under my supervision, in the
School of Chemical
Sciences at NISER, Bhubaneswar, India.

Signature of Thesis Supervisor

School: SCS
Date: 25/04/2024
 ACKNOWLEDGEMENT

I would like to take opportunity to express my profound gratitude and deep

regards to my guide Dr. Nagendra Ku. Sharma, for his exemplary
guidance and cordial support throughout the course of this project.

I would also like to extend my deep sense of gratitude to all of my senior

labmates for their constant guidance and valuable suggestions during the
project. I am also highly obliged to my senior lab mates for their
constructive suggestion and cooperation during the entire period.

Moreover, I am grateful to National Institute of Science Education and

Research (NISER), for providing the necessary infrastructures and
facilities. I would also like to thank Disha for providing this great
opportunity and their extending support

At last, I am grateful to my family and friends for their encouragement and

support.
 ABSTRACT

This study focuses on the synthesis of novel spiro and oxa spiro compounds
utilizing hyper-valent iodine reagents. The synthetic route involves the
transformation of tryptophan containing dipeptides into complex spiro
compounds, leveraging the versatility and efficiency of hyper-valent iodine
chemistry. Following synthesis, the newly developed compounds are
subjected to biochemical evaluation to assess their potential anti-cancer
properties. In silico methods are employed for this purpose, utilizing
computational tools and algorithms to predict the compounds' interactions
with relevant biological targets involved in cancer pathways.By employing
molecular docking and virtual screening techniques, we aim to elucidate the
binding affinities and modes of action of spirocycles against cancer-related
proteins. The results obtained from in silico analyses provide valuable
insights into the molecular mechanisms underlying the anti-cancer potential
of spirocycles, guiding future experimental studies and facilitating the
development of novel therapeutic agents for cancer treatment.The study aims
to identify promising candidates with anti-cancer activity, providing insights
into the molecular mechanisms underlying their efficacy and potential for
further development as therapeutic agents.
 Table Of Contents

Declaration…………………………………………02
Acknowledgment…………………………………..03
Abstract…………………………………………….04
Table of contents……………………………………05
List of abbreviations………………………………..06
Introduction…………………………………………07
Results and Discussion……………………………..10
Spectral Datas………………………………………14
Conclusion and future plan…………………………21
List of references……………………………………22
 LIST OF ABBREVIATIONS

⚫ 1
H Proton
⚫ 13
C Carbon-13
⚫ DCM Dichloromethane
⚫ MeCN Acetonitrile
⚫ DMF N, N-dimethylformamide
⚫ EtOAc Ethyl acetate
⚫ MeOH Methanol
⚫ CDCl3 Chloroform-d
⚫ Rt Room temperature
⚫ TLC Thin Layer Chromatography
⚫ RB Round Bottom Flask
⚫ Ts p-toluenesulfonyl (tosyl
⚫ min minute(s)
⚫ Mol mole(s)
⚫ mL milli litre
⚫ μL micro litre
⚫ μM micro molar
⚫ mM milli molar
⚫ mp melting point
⚫ NMR Nuclear Magnetic Resonance
Introduction

Tryptophan, an essential amino acid, serves as a fundamental building block for protein synthesis and
is integral to various physiological processes within the human body. Beyond its role in protein
metabolism, tryptophan plays a pivotal role in neurotransmitter synthesis, immune function, and
regulation of mood and behavior. As the precursor to serotonin, a neurotransmitter known for its role in
mood regulation and emotional well-being, tryptophan influences aspects of cognition, mood stability,
and sleep patterns.Moreover, tryptophan's metabolic pathways give rise to several bioactive compounds
with diverse physiological functions. One such pathway leads to the synthesis of niacin (vitamin B3),
essential for energy metabolism and DNA repair. Additionally, tryptophan catabolism via the
kynurenine pathway yields metabolites that modulate immune responses and inflammation.Given its
multifaceted role in human physiology, tryptophan and its derivatives have garnered significant
attention in the development of therapeutics, particularly in the realm of psychiatric disorders, sleep
disturbances, and immune-related conditions. Tryptophan-containing drugs and supplements hold
promise in addressing deficiencies or dysregulations in tryptophan metabolism, thereby offering
potential therapeutic benefits across a spectrum of disorders.

Tryptophan contains a indole moiety.Indole is a prevalent phytoconstituent found in many plant species
and generated by many different kinds of microorganism .Indole-derived phytoconstituents and
bacterial metabolites are produced by the biosynthesis of tryptophan with other amino acids. As a result,
it is found in flower scents, pharmacologically active indole alkaloids, and certain animal hormones like
serotonin and melatonin. Some naturally occurring indole alkaloids have received FDA approval,
including vincristine, vinblastine, vinorelbine, and vindesine for anti-tumor activity; ajmaline for anti-
arrhythmic activity; and physostigmine for glaucoma and Alzheimer's disease. The success of the
above-mentioned compounds demonstrates the usefulness of the ring system in multidisciplinary
disciplines, including the pharmaceutical and agrochemical industries.

Spiro Heterocycles : A Potent Anti-Cancer Drugs

Spiro oxindoles and oxa spiro oxindoles have emerged as promising contenders in the realm of
anticancer research, offering novel avenues for therapeutic exploration. These compounds,
characterized by their unique spirocyclic structures, exhibit remarkable biological activities, particularly
in the context of cancer treatment. With their diverse chemical compositions and versatile
pharmacological profiles, spiro oxindoles and oxa-spiro oxindoles hold immense potential as potent
anticancer reagents. Their ability to modulate key cellular pathways implicated in cancer progression,
coupled with their favorable pharmacokinetic properties, underscores their significance as promising
candidates for the development of next-generation anticancer therapies. In this introduction, we delve
into the burgeoning field of spiro oxindoles and oxa spiro oxindoles, exploring their structural diversity,
mechanisms of action, and preclinical evidence supporting their role as effective anticancer agents.

Due to the harmful effects of existing anticancer drugs and the limited effectiveness of chemotherapy,
the quest for potent and targeted antitumor agents remains a focal point in organic medicinal chemistry.
Targeted therapy, a modern approach to cancer treatment, utilizes drugs tailored to disrupt specific
molecules crucial for tumor growth and advancement. Among these developed anticancer therapeutics
molecules, spirocyclic oxindoles, particularly spiro-oxindoles, have emerged as highly effective
compounds. They possess a rigid heterocyclic ring fused at the 3-position of the oxindole core, with
various substitutions around it. These compounds demonstrate notable inhibition of cell proliferation
and induction of apoptosis in cancer cells, resulting in complete regression of tumor growth while
sparing normal cell activities. The development and recent advancements in diverse spiro-oxindole
derivatives as potent and selective inhibitors of p53-MDM2 interaction which generally helps in cell
apoptosis, focusing on spiro-pyrrolidinyl oxindoles, their mechanism of action, and structure-activity
relationship. It contributes to understanding how spiro-oxindoles reactivate p53 in tumor tissues and
aids in the design of more potent analogs with enhanced efficacy and reduced side effects for cancer
treatment. Recent advancements in spiro-oxindole derivatives as potent small molecule inhibitors of
p53-MDM2 interaction, valuable as anticancer agents.

In recent decades, the study of spirocyclic compounds has garnered significant interest due to their
unique structures, which give rise to a diverse array of physiologically active chemicals, natural
products, and essential intermediates in organic synthesis. Examples such as (-)-spirocalcaridine A,
carijodienone, and spirodactylone highlight the broad scope of spirocyclic chemistry and its potential
applications. This interest has led to the establishment of numerous synthetic procedures for the
production of spiro compounds, confirming that their molecular construction is attainable with suitable
resources.

Spiro rings, including spiro ketals, are prevalent in natural products, with simple spiro ketals even
serving as insect pheromones. Beyond their natural occurrence, spiro-containing medications have been
the subject of extensive research, with recent studies focusing on novel synthetic pathways to
incorporate spiro scaffolds into pharmaceutically active compounds. The three-dimensionality and
structural uniqueness of spiro compounds offer advantages for patentability, distinguishing them from
aromatic compounds. Moreover, while both spirocyclic and aromatic rings can influence ligand binding
entropy, compounds with too many flat rings may exhibit inferior physical characteristics and are less
likely to be developed as medications, further emphasizing the appeal of spiro compounds in drug
discovery.

Recent clinical trials have focused on small molecule protein/protein interaction inhibitors targeting the
MDM2/p53 connection, a critical pathway in cancer biology. Notably, Wang's team at the University of
Michigan identified a new family of spirooxindole-based inhibitors with exceptional potency. These
compounds demonstrated remarkable activity in human cancer xenograft models following oral
treatment, with one compound emerging as the most effective MDM2 inhibitor reported till now.
Another family of inhibitors, based on the spiroisoxazoline oxindole scaffold, demonstrated disruption
of the p53/MDM2 complex in live-cell biomolecular fluorescence complementation assays, further
highlighting the therapeutic potential of spiro-containing compounds in cancer treatment.

In summary, the burgeoning field of spirocyclic chemistry holds promise for the development of novel
therapeutics, particularly in oncology. The remarkable potency and diverse mechanisms of action
exhibited by spiro compounds underscore their significance in drug discovery and highlight avenues for
further research and clinical development.
Importance Of Hypervalent Iodine(lll) in Synthesis Of Spiro Compounds
Hypervalent iodine reagents(III) have been widely used in various oxidative coupling processes
during the last several decades. Surprisingly, significant attention to dearomatization triggered
hypervalent iodine reagents(III) C-O bond formation. attention as a strong tool for gaining access to
difficult information molecules. A limited, on the other hand, A lot of research on I(III) were reported.
C-O bonds are created and mediated by carbon without dearomatization. for example,Saurz used the
PIDA/I2 system fo photochemical reaction type cross-coupling in which a 1,5-hydrogen transfer occurs
in a free radical system. Kita discovered an oxidative lactone formation by a comparable C-H
abstraction strategy.

In comparison to conventional heavy-metal oxidants, hypervalent iodine (III) reagents, also

known as "3-iodanes," have received a great deal of attention over the last three decades because they
are abundant, stable, non-toxic, environmentally friendly, and mild 2e oxidants with a wide range of
applications. They constantly endorse deformed trigonal bipyramidal geometry with electronegative
ligands in the axial positions a less electronegative aryl ring and two lone pairs of electrons in the
equatorial positions. The node in a hypervalent nonbonding orbital, a 3-center-4-electron (3c-4e) bond
(L-I-L), generated by the overlap of the iodine atom's 5p orbital with the orbitals of two ligands, makes
hypervalent iodine (III) reagents electrophilic .

Many novel heterocyclic compounds, such as phenyliodine(III)

bis(trifluoroacetate), phenyliodine(III) diacetate, and iodosobenzene (PhIO), have been developed as a
consequence of the extensive use of hypervalent iodine (III) reagents to build carbon-carbon, carbon-
hetero atom, and hetero-hetero atom bonds. The hypervalent iodine compound (diacetoxyiodo)benzene
(PhI(OAc)2), also known as (DAIB) or phenyliodine(III) diacetate (PIDA), is frequently used in
organic chemistry as an oxidizing agent . Furthermore, (diacetoxyiodo)benzene is used in a variety of
pharmaceutical intermediates, liquid crystal display (LCD) polarizing films, industrial, human, and
animal nutrition products, and other applications.

Bioactive Tropolonoid Natural Products

Tropolones are aromatic compounds with a unique seven-membered ring structure containing adjacent
carbonyl and hydroxyl groups. They represent the first discovered non-benzenoid aromatic system,
characterized by a stable partial positive charge at the carbonyl carbon. Tropolone exhibits dynamic
tautomeric behavior, shifting between two states due to the movement of the hydroxyl proton between
its functional groups. Natural tropolonoid compounds like colchicine possess a range of beneficial
properties including antibacterial, antifungal, antiviral, and antitumor effects. Tropolone demonstrates
bacteriostatic and bactericidal actions, while puberulic acid may have antimalarial properties.
Tropolonoids exert their effects by selectively inhibiting enzymes through chelation with metal ion
cofactors such as zinc, magnesium, and manganese. Although colchicine has a long history of use as
both a poison and a remedy for gout arthritis, recent FDA approvals are primarily due to concerns
regarding its overall toxicity and its limited efficacy in treating cancer.

Thujaplicins, also known as 'hinokitiol' in eastern Asia, are antifungal isopropyl-tropolones used as
preservatives for mushrooms, flowers, and vegetables. 'Hinoki' oil is used in cosmetics in Japan and
Russia to prevent hair loss and thinning. Thujaplicin analogues with cytotoxic action and
metalloprotease inhibition include -dolabrinol and 4-acetyl tropolone. Purpurogallin, an anti-oxidant
activity.

Objective of this work

We have synthesized Spiro Oxindoles using metal ion free method using hypervalent iodine(iii)
reagents such as Phenyl iodoacetate, inspired by the importance of spiro compounds in medicinal
chemistry and its biological activities. We have also synthesised Non benzenoid fused Spiroccyclic
compounds considering their biological importance.We have performed In Silico Studies Of these
Compounds with cell death inhibitor protein (PDB :6R3K) and human breast cancer protein
(PDB:4OAR) discovered that this chemicals have critical biological activity and functions as an anti-
tumor or tumor suppressor agent. We've also synthesised Tryptophan containing Dipeptides, which
make the corresponding spiro molecule. This molecule also has fluorescent activity, and this enables us
to determine the presence of drug activity inside the cell using cell imaging.

Result And Discussion

In this report we will be discussing our work on synthesis of Spiro and Oxa spiro oxindole
compex. We began the synthesis of Boc (tert-butyloxycarbonyl) protection of different L-amino
acids (, tryptophan, histidine, glycine, alanine). Then we have perpared tryptophan methyl ester
by using thinoyl chloride and methanol.Then by peptide coupling reaction we have synthesized
corresponding dipeptides having trypton moiety in it.
Then by hydrolying these derivatives we got the respective starting material for the synthesis of
Spiro oxindole and its derivative.
Protection of amine

Esterification of Tryptophan

Scheme-1a-Synthesis of Oxa Spiro Oxindole

 Scheme-1b : Sythesis of Spiro Oxindole from Boc-Trp

Crystal Structer of Oxa-Spiro oxindole

Scheme1c:Synthesis Of Tropolone fused spiro oxo-indole

 Crystal Structer of Tropolone fused spiro oxo-indole

Experimental Section

Materials and Instrumentation:

All required materials were bought from commercial suppliers and were used without further
purification. Dry solvents used in this scheme (DMF, MeOH, DCM) were prepared freshly using
distillation. Reactions were monitored by thin layer chromatography TLC, visualized by UV and
ninhydrin. Chromatography for each reaction were performed using 100 – 200 mesh silica. Bruker
AV (400MHz, 700MHz) was used to record NMR spectra. 1H and 13C NMR chemical shift were
recorded in ppm taking tetramethyl silane a reference. Splitting patterns are abbreviated as: Singlet
(s); Doublet (d); Doublet of doublet (dd); Triplet (t); Quartet (q); Multiplet (m),

Synthesis of Boc-Trytophan:

To synthesize Boc-tryptophan (N-alpha-boc-tryptophan), begin by protecting the amino group of

tryptophan with a Boc (tert-butoxycarbonyl) group. This is typically achieved by reacting tryptophan
with Boc anhydride in a suitable solvent, such as dichloromethane or 1,4Dioxane, under basic
conditions, such as with a tertiary amine like triethylamine. The reaction is generally carried out at a
low temperature to minimize side reactions. Once the Boc-tryptophan is obtained, it can be purified by
methods like crystallization or chromatography. The Boc group serves to protect the amino group
during subsequent reactions, allowing for further functionalization or peptide synthesis.

Synthesis of Tryptophan Esters

Weigh the desired amount of the esterification reagent (e.g., acyl chloride, acid anhydride, or acid
chloride) in a separate container. To catalyze the esterification reaction, add this reagent to the
Tryptophan solution and a base (such as pyridine or triethylamine). Throughout the process, maintain
an anhydrous atmosphere. Stir the reaction mixture at an appropriate temperature for esterification to
occur, and after completion, add an acid to quench excess reagents and byproducts. The organic layer is
extracted, washed with water, and the solution is concentrated. Purify the crude product using
procedures such as column chromatography, and confirm the product's identity using analytical
techniques such as NMR, IR, and mass spectrometry. Keep the synthesized Tryptophan ester in a
suitable container, away from light and moisture.

Synthesis of Tryptophan containing Dipeptides

Boc prptected amino acid (1 equiv) was dissolved in commercially purchased anhydrous DMF,
followed by addition of NMM (3 equiv). Resulting solution was cooled to 0 °C, and EDC.HCl
(1.2 equiv) was added, followed by addition of HOBt (1.2 equiv) and l-methylated tryptophan.
Then, the reaction mixture was removed from the ice bath and placed in a heating bath at 55 °C
for 8 h. After completion, the reaction mixture is concentrated under reduced pressure and
extracted with ice water and ethyl acetate for (× 3). The organic layer is dried over Na2SO4
and concentrated under reduced pressure. The concentrated crude mixture was purified by
column chromatography with organic solvent hexane and EtOAc. Hydrolysis of the ester group
is performed by LiOH for 8 h at room temperature.

Synthesis of Tosyl tropolone :

5 g of Tropolone, dissolved in DCM is taken in an Round bottom flask Triethyl amine (0.122mmol,
17.12ml) was added to it with continuous stirring using a micropipette. It is then kept under an ice bath
and TsCl (1.5 eq) is added dropwise to the reaction mixture. After 5- 10 minutes the reaction mixture
was warmed to room temperature and kept in N2 atmosphere with continuous stirring for overnight. It
is then evaporated under reduced pressure. Hexane is added to the crude reaction mixture so that all of
the impurities get dissolved. It is then decanted and the process is repeated for 2-3 times till the solution
turns colourless. The remaining solvent is also evaporated and dried in high vacuum. The compound (1)
obtained was pure, light brown coloured with 98% yield, with no further purification.

Synthesis Of Tropolone Fused Tryptophan Ester

Tosyl Tropolone was taken in a Round bottom flask (1eq.) then we have added Ethanol and Stir the
reaction mixture untill the Tosyl Tropolone disolves firmly. Then add Triethyl amine (3eq. ) and then
add Tryptophan ester (1.2 eq.) .Stir the reaction for 12 hours in reflux at 900C .After the comlipition of
the reaction evaporate the solvent and do extraction in Ethyl acetate medium. Then after filteration
using column chromatography we got then desired compound at Rf 0.67 and its and dark yellow
colored product and also have mild florescent property.
(Methyl Ester)1H NMR (700 MHz, CDCl3) δ 8.56 (d, J = 11.1 Hz, 1H), 7.67 (d, J = 7.5 Hz, 1H), 7.58 (d, J = 7.9 Hz, 1H),
7.32 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 8.9 Hz, 1H), 7.16 (dd, J = 9.0, 7.4 Hz, 2H), 7.11 (dd, J = 16.5, 8.8 Hz, 2H), 7.06 (s,
1H), 6.67 (t, J = 9.4 Hz, 1H), 6.39 (d, J = 10.4 Hz, 1H), 4.54 (dd, J = 12.8, 7.1 Hz, 1H), 3.66 (s, 3H), 3.45 (ddd, J = 52.6,
15.5, 6.1 Hz, 2H).
(Ethyl Ester)1H NMR (400 MHz, CDCl3) δ 8.67 (s, 1H), 7.68 (d, J = 7.3 Hz, 1H), 7.60 (d, J = 7.7 Hz, 1H), 7.33 (d, J =
7.8 Hz, 1H), 7.25 (dd, J = 12.9, 6.9 Hz, 1H), 7.12 (ddd, J = 20.7, 14.4, 5.6 Hz, 5H), 6.67 (t, J = 9.3 Hz, 1H), 6.40 (d, J =
10.3 Hz, 1H), 4.53 (dd, J = 12.7, 7.0 Hz, 1H), 4.20 – 4.05 (m, 2H), 3.45 (ddd, J = 21.7, 14.6, 6.1 Hz, 2H), 1.14 (t, J = 7.1 Hz,
3H).

Spectral data and Analysis

Docking studies of Spiro cyclic compounds

The rapid increase in the number of proteins with known three-dimensional structures is partly due to
advancements in structural determination tools like high-throughput X-ray crystallography, with
structural genomics projects contributing to this trend by making structures publicly available. Many of
these proteins are chosen for their therapeutic potential through large-scale initiatives led by genomics
collaborations. Computational methods, particularly high-throughput docking, play a significant role in
drug development programs, especially when only the structure and active site of a target are known.

Docking involves predicting the configuration and orientation of ligands within a specific binding site,
aiming for precise structural simulation and efficient activity prediction. However, understanding the
chemical features governing biological recognition or predicting compound alterations that enhance
potency are complex challenges. Docking is typically approached in multiple phases, each adding
complexity to the process. Initially, docking algorithms are employed to position small molecules at the
activation site.

The TP53 gene, encoding the p53 protein, is a critical tumor suppressor involved in regulating cell
growth and division, with mutations often linked to cancer development. p53 acts as a transcription
factor, coordinating cellular responses to stressors like DNA damage. Wild-type p53 halts the cell cycle
to allow DNA repair or induces apoptosis if damage is severe. Mutated p53, common in cancers, can
lose tumor-suppressive functions and gain pro-survival properties, disrupting cell regulation and
promoting cancer progression. Ligand docking helps understand interactions between small molecules
and p53, aiding in identifying compounds that modulate its activity, potentially targeting apoptosis
regulation in cancer cells by enhancing pro-apoptotic functions or inhibiting gain-of-function mutations.

When the human cell death inhibitor protein is being docked with Spiro oxoindole it gave promising
results. The binding affinity was about -9.0 kcal per mol and it docked in the binding sites of the
protein.The interaction between receptor and ligand complex are very strong. In shows many covalent
interaction with Ala, Asp,Tyr,Ila,Ser, units of the protein .The receptor and ligand interaction diagram
and the 3d view of binding are shown below.When the ligand binds to its receptor, it forms a complex
through a series of non-covalent interactions such as hydrogen bonding, van der Waals forces,
electrostatic interactions, and hydrophobic interactions. These interactions occur between specific
regions of the ligand and complementary binding sites on the receptor, resulting in the stabilization of
the ligand-receptor complex.

The binding process typically involves several steps, including recognition, binding, and
conformational changes in both the ligand and the receptor. The strength and specificity of the
interaction between the ligand and receptor determine the biological response triggered by the complex.
Additionally, the binding affinity of the ligand-receptor complex influences its stability and duration of
action.Understanding the interaction between a ligand and its receptor is crucial for drug discovery and
design, as it allows for the rational optimization of ligand structures to enhance binding affinity,
selectivity, and therapeutic efficacy. Computational methods such as molecular docking and molecular
dynamics simulations are often employed to study and characterize the ligand-receptor interaction at
the atomic level, providing valuable insights into the molecular mechanisms underlying biological
processes and drug action.
 Ligand Binding Affinity Mode RMSD(L) RMSD(U)

Spiro oxo_1 -9.0 0 0 6

Spiro oxo_2 -9.0 1 1.237 8.876

Spiro oxo_3 -8.8 2 2.678 6.496

Spirooxo_4 -8.6 5 1.987 8.543

Spiro oxo_5 -7.8 4 2.582 5.980

Spiro oxo_6 -6.7 6 3.568 7.98

\
Spiro oxo_7 -6.5 7 2.98 8.98

Future Plans
As we have found that spiro compound were revolutionary drug possessing high anti tumor, anti
microbial, anti fungal activies synthesis of these compounds in a more economically feasible way can
resolve the problem. We have to synthsize a large no. of substrates which includes tryptophan esters,
dipeptides of typtophan and enamines. The reaction needs optimization of solvents and the reagents
used. Circular dichroism can suggest the secondary structer of the tryptphan containg dipeptides and
also we have ro do cell imaging . Many docking studies needs to performed with the synthesised spiro
oxoindoles compound.
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