Laxmi GenChem Chemistry Presentation

Welcome To

Laxmi GenChem

-Solution for Healthier Life

1

-

2e-mail: [email protected] www.Laxmigenchem.com

ManagementManagement

Laxmi GenChem -

Solution for Healthier Life

Mr. Vijaya Madhava Reddy.V is Business Director of Laxmi

GenChem Pharma Ltd completed M.Sc in Organic Chemistry from

Osmania University and had 13 years Industrial Experience in

Synthetic Chemistry and Project Management in CRO & API area in

various MNC’s in Hyderabad. Mr. Reddy was also a former Research

Student from Masaryk University, Czech Republic, Europe.

Mr. Jagan Mohan.G is Managing Director of Laxmi GenChem Phama

Ltd completed M.Sc in Organic Chemistry and had 12 years Industrial

Experience in Synthetic Chemistry , CRAMS, Medicinal Chemistry &

API area in various MNC’s in Hyderabad. Mr. Jagan led Laxmi

GenChem through the initial phases of evolution with remarkable

success. He is responsible for putting the right scientific talent,

leadership, processes and infrastructure in place to ensure

continuous growth.

Over ViewOver View Laxmi GenChem is a dynamic custom synthesis and contract research organization to support globally located pharmaceutical / biotech companies.

We combine Science, Innovation and People to help our clients address their drug development challenges.

New frontiers require new ways of working and we believe that to deliver the true promise of science, innovation is necessary.

Our customers benefit not just from lower costs and boosted efficiencies, but also from the infusion of fresh ideas and thinking.

3e-mail: [email protected] www.Laxmi GenChem.com

Laxmi GenChem -


Vision & MissionVision & Mission Laxmi GenChem would be a global leader in pharma services. Deliver value-added scientific services with speed and quality. Customer Focus - Change expected to exceptional. Customer once client forever. Strive to exceed expectations through innovative solutions. Committed to business and scientific integrity. Open, Fair, Honest and Transparent behavior. Give to get, give before you expect. Respect for individuals, property and timelines. Commit to Excel - In every act and deed Best always. Relentlessly and continuously improve ourselves and our solutions. Teamwork and Leadership Work Together…Win Together. A collective effort to be the leader in the chosen field


Laxmi GenChem -


Why Laxmi GenChem?Why Laxmi GenChem?

Product Design & Development. Highly professional and experienced research team. Outstanding skills on difficult chemistry. Cost-effective services. On -time delivery Projects. Timely Communicative (Weekly Reports & Tele Conference). Data Base Management & Project Management Flexible for customer: we operate as your own chemistry department.


Laxmi GenChem -


Research & Development CapabilitiesResearch & Development Capabilities

Synthesis of Medicinal chemistry Analogs, Libraries & Scaffolds. Custom synthesis of target compound/processes. R &D Process Optimization. Collaborative research. Intermediate scale (milligram scale to Multi Kilogram Scale). Special building block collections in house. Skilled at making constrained, complex analogs. Skilled at creating new synthetic routes. Project Management and Documentation.


Laxmi GenChem -


ExpertiseExpertise

Alkylation, Acylation, Halogenations, Amidation, Condensation, Cyanation, Cyclo-condensation, and Formylations etc. Organo-Metallics- Alkyl Lithium (Metallation – MeLi / n-BuLi / LDA), Grignard reaction, Organoborane and Silylation reaction etc.. Palladium Chemistry: Suzuki, Sonogashira, Heck, kumada, Stille, Carbonylation and Buchwald couplings etc.. Hydrogenation using Pd/C, Pt/C, Rh/C and Rani-Ni etc.. Synthesis of Protected N-Terminal & C- Terminal Amino Acids Scaffolds & Di-peptides, Cyclic Peptides. Nucleoside chemistry: Modification of Nucleoside bases , Metal Mediating Reactions on Nucleosides, Modification of Sugar Moieties, Alkylation, Fluorination Reaction at Nucleosides Based and Sugar Moieties etc.. Asymmetric syntheses, Chiral alkylation, Chiral Amines syntheis, Enantio selective catalysis ,Chiral auxiliaries and Chiral resolution of racemates etc.. Wittig Reaction, Mitsunobu Reaction and Vilsmeier-Hack reaction etc.. Oxidation – Jones, Swern, Dess-Martin Oxidation, KMnO4, NaIO4, OsO4 and K2CrO4 etc. Reductions – Catalytic, Metal hydrides, High pressure,Birch reductions, Diborane, LAH, DIBAL-H and NaCNBH3 etc. . Beta-Lactam Antibiotices, Macrolides, Steroids and Prostaglandins. Special building blocks, API reference standards and Impurity standards. Milligram to Kilogram synthesis of complex organic molecules. Low to high temperature chemistry.

7

Laxmi GenChem -


Collaboration ModelsCollaboration Models

Full time equivalent (FTE)

Fee for service (FFS) per library

Single price per compound


Laxmi GenChem -


ServiceService Contract Research Organization (CRO)

Medicinal Chemistry/Synthetic Organic Chemistry. Library Synthesis/ Parallel Synthetic Chemistry. Nucleoside/Sugar Chemistry. Amino Acid/ Peptide Chemistry. Asymmetric/ Chiral Chemistry. Material Chemistry.

Custom Research & Manufacturing Services (CRAMS)

API Intermediates and Impurities ( Non-GMP)

9e-mail: [email protected] www.LaxmiGenChem.com

Laxmi GenChem -


Medicinal Chemistry/Synthetic Organic Medicinal Chemistry/Synthetic Organic ChemistryChemistry

Laxmi GenChem have extensive experience in synthesizing compounds designed by medicinal chemists at our clients’ site. Our major focus is given on productivity (milligram to kilogram scale) and cycle time management in these efforts with real time problem solving in synthesis.

Medicinal Important compound. Biologically active Compounds. Metabolites, Antibiotics and Macrolides. Steroids and Prostaglandins. API reference standards and Impurity standards

After completion of the project all the experimental reports would captured into Word format (doc or docx) or Structural Database (SD) according Client defined format.


Laxmi GenChem -


Library Synthesis/ Parallel Synthetic ChemistryLibrary Synthesis/ Parallel Synthetic Chemistry

Laxmi GenChem have extensive experience in synthesis of a variety of libraries ranging between focused libraries 10-30 members to large 2000 member libraries, scaffolds/building blocks including complex structure involving multi-step synthesis in milligram to kilogram scale with complete characterization, lead generation, lead optimization and SAR libraries generated in 5-50 mg scale with > 90% purity of LCMS. After synthesis of the library compounds, Laxmi GenChem would capture all the synthetic procedure into SAR tables and Structural Database (SD) format in Client defined format.


Laxmi GenChem -


Nucleoside/Sugar ChemistryNucleoside/Sugar Chemistry Development of novel methodologies for the synthesis of modified nucleobases and nucleosides Medicinal chemistry of analogues of nucleobases and nucleosides. Design and synthesis of novel C-nucleosides for chemical biology. Synthesis of modified nucleoside triphosphates Novel fluorescent nucleoside labeling for bioanalytical applications. Chemical biology of base-modified nucleic acids. Click Reaction Applications in Nucelobases. Metal Mediating Reactions on Nucleosides (Suzuki, Sonogashira, Heck, Kumada, Stille, Carbonylation and Buchwald couplings) Modification of Sugar Moieties


Laxmi GenChem -


Amino Acid/Peptide Chemistry Amino Acid/Peptide Chemistry Protected N-Terminal & C- Terminal Amino Acids Scaffolds & Di-peptides, Cyclic Peptides. Asymmetric/ Chiral Chemistry Chiral alkylation, Chiral Amines syntheis, Enantio selective catalysis, Chiral auxiliaries and Chiral resolution of racemates. Material Chemistry/Polymer Chemistry Photoactive conducting polymers, charge transporting polymers External stimulii small molecules. Organic Light-Emitting Diode (OLED) Materials Solar Cells: Dye-Sensitized Solar cells and Organic photovoltaic, cells, Conducting Polymers, Organic Dyes.


Laxmi GenChem -


Custom Research & Manufacturing Services Custom Research & Manufacturing Services (CRAMS)(CRAMS)

At Laxmi GenChem ’ facilities, highly skilled chemists routinely carry out syntheses of complex intermediates and final products With/without technology transfer; starts with process development/optimization and approval of lab sample, followed by commercial validation campaign, regulatory filing and approval and then the long-term commercial supply.

Process Development. Route Optimization. Manufacturing. Validations. Impurities – identification, characterization and synthesis. 14e-mail: [email protected] www.Laxmi GenChem.com

Laxmi GenChem -


API Intermediates and ImpuritiesAPI Intermediates and Impurities

Laxmi GenChem process development chemists are specializing in the design and optimization of synthetic routes for gram to multi-kilo quantities of compounds suitable for the transfer of laboratory procedures into the pilot plant. We aim to develop scalable, safe and economical solutions.

Route of synthesis- optimization and validation Custom research and manufacturing process Scale-up & optimization intermediates and related chemicals Scale up from lab to pilot and pilot to commercialization (mg level to 1000kg level) Impurity profiling.


Laxmi GenChem -


Laxmi GenChem Project Managment Request for Proposal (RFP) EvaluationRequest for Proposal (RFP) Evaluation

Laxmi GenChem quotes best cost effective pricing model that includes “Synthesis of Target Compound, Purification and Analysis, Literature Support, Chemical sourcing and shipping and Project management tools between Laxmi GenChem and the client” or between Laxmi GenChem and the client’s CRO. Laxmi GenChem CRO scientific team is capable of provides a best Route of Synthesis (ROS) and alternative of ROS for target compounds based on literature.

Execution of ProjectExecution of Project

Laxmi GenChem CRO scientific team consists of experienced Ph.D and Master Students, who have ability to synthesis the target molecule in stipulated timelines. Laxmi GenChem always keeps 20% buffer back up team for project. Our pioneer Group leader will prepare weekly reports and arranges a tele-Conference with Client on weekly basis. All the intermediates and final Compounds are analyzed characterized by NMR and LCMS purity. After completion of Project, Laxmi GenChem project Management team will provides Final reports in Word format (Doc & Docx) and Structural data format (SDF & Excel) documentation in Client defined format.


Laxmi GenChem -


Time LinesTime LinesTime lines For QuoteTech Pack is Available : 24- 48 hrTech Pack is Not Available : 48- 72 hr

*Based on Chemical Sourcing information time lines may vary.

Time lines For Target CompoundsTime lines For Target Compounds Laxmi GenChem Chemistry team can deliver target compounds

Single target : 3-4 weeks Scaffold : 4-6 weeksLibrary : 6-8 weeks

*Based on complexcity of compoud time lines may vary. 17e-mail: [email protected] www.Laxmi GenChem.com

Laxmi GenChem -


Quality PolicyQuality Policy

Being on time every time to meet our client's needs. Consistently meeting or exceeding our client's quality requirements. Continuous improvement of our systems and processes. Ensuring proper training of our people so as to better serve our

clients. Recognizing that quality is not just another goal, but a basic strategy

for survival and growth.


Laxmi GenChem -


19

Quatations for Med.Chem; API & CRAMS

Trackers ( i.e Project; Reagent; Dispatched & SAR).

Final ReportsFinal Reports

Intermediate Inventory

NMR- FID CollectionNMR- FID Collection

Monthly Evaluation tracker

MOM

Project Management- ToolsProject Management- Tools

e-mail: [email protected] www.LaxmiGenChem.com

Laxmi GenChem -


20

Tracker are historical record for a particular program.It shows status of all the Ongoing, Holed and Completed targets status in a structured format.It is also act as demonstrative tool at Scientific end, BD end and Client end.

Why Do we need tracker?Why Do we need tracker?

e-mail: [email protected] www.Laxmi GenChem.com

Laxmi GenChem -


21

What Kind of Information we do find in What Kind of Information we do find in TRACKER?TRACKER?


Laxmi GenChem -


22

Project Management- Final Project Management- Final ReportReportPreparation standard Template for Final report. ( Preparation standard Template for Final report. ( i. i.

ee JOC format) JOC format)Preparation of finalPreparation of final reports for all dispatched reports for all dispatched

targets.targets.Once compound has been dispatched, time final Once compound has been dispatched, time final

report has to prepare including Analytical reports report has to prepare including Analytical reports

with in the 2 weeks.with in the 2 weeks.All Final report will be send to Corresponding group All Final report will be send to Corresponding group

leaders for final proof reading then will be updated in leaders for final proof reading then will be updated in

Client e-room. Client e-room. Dispatched details in SDF format

Laxmi GenChem -


e-mail: [email protected] www.Laxmi GenChem.com 23

Intermediate InventoryIntermediate Inventory Identify the all key SM and intermediates and Reagents for every finished target. Record the information about all key intermediates, key SM and Reagents all finished target. This Process is very much use for Scaffold and Library Synthesis.

Minutes Of Meetings (MOM )Minutes Of Meetings (MOM ) Organize Tele-Conference with Scientific Team, BD & Client.Identification of the keys inputs and constraines from Both Sides. Record the MOM and updated to Scientific Team, BD & Client.

Laxmi GenChem -


Thiazole- Sulfonamide Derivatives Thiazole- Sulfonamide Derivatives BrEtO

O

O

H2N NH2

S

N

S

OEt

O NH2 N

S

OEt

O NH2

Br

N

S

OEt

O

Br

N

S

OEt

OHO INT-A

NS

OEtO

S NO

O

F F

Cl

NS

OH

S NO

O

F F

Cl

NS

O

S NO

O

F F

Cl

Dess-Martin Oxidation

NSS N

O

O

F F

Cl

EtO O

wittig Reaction

Mitsunobu

NSS N

O

O

F F

Cl

EtO O

NSS N

O

O

F F

Cl

HO O

1 2 3 4 5

6 7

8 9

Et-2-Br-Pyruvate

IO

OAcAcOOAc

O

INT-A

SNH O

OF

F

ClNH2

FFS Cl

O

O

Cl

Py

BrominationDe-Amination Grignard

Reduction Hydrolysis

Diazatization

NS

NH

S NO

O

F F

Cl

R

R-NH2/Na(OAc)3BHDIBAL/THF

NBS/ACNNaNO2/H2SO4

7

iPrMgBr/CH3CHO

THF/ -70oC to - 40oC DEAD/TPP/Toulene

Reductive AminationCH2Cl2

THF

Pd/C/EtOAc LiOH/H2O/THF

H3PO2Heat

NSS N

O

O

F F

Cl

HN OR

EDC/HOBt/DMF

R-NH2

Coupling Reactioin

10

-70oC to RT

1.LiOH/H2O/THF2.EDC/HOBt/DMF

NS

NH

O

S NO

O

F F

Cl

R

R-NH2


A A Potent Janus Kinase 2/Fms-Like Tyrosine Kinase-3 Potent Janus Kinase 2/Fms-Like Tyrosine Kinase-3 (JAK2/FLT3) Inhibitor(JAK2/FLT3) Inhibitor

N,O,O-Hetero Macro cyclic compounds

N,N,O-Hetero Macro cyclic compound

N

NO

N

O

O

NH

N

N

O

ON

O

O

NH

N

N

N

NH

O


N,O,O-Macro Cyclic Compounds-N,O,O-Macro Cyclic Compounds-Retro SynthesisRetro SynthesisDisconnection Approach- RCM Route

Disconnection Approach- Non-RCM Route

N

NO

N

O

O

NH

1

2

3

4

5

3

6

N

N

O

ON

O

O

NH

1

2

4

53

3

6

N

NO

N

O

O

NH

1

2

3

4

5

N

N

O

ON

O

O

NH

1

2

3 5

6

4


N,O,O-Macro Cyclic CompoundsN,O,O-Macro Cyclic CompoundsN,O,O-Macro Cyclic-RCM Route

28

CHOOH

O2N

Cl Cl CHOO

O2N

ClO

O2N

Cl

HOBr O

O2N

Cl

O

5-Nitro Salicylaldehyde

O

O2N

N

ONH

O

H2N

N

O

N

N

Cl

OH

INT-B

N

N O N

O

O

NH

1 2 3 4

5 6 Target

INT-A

N

N

Cl

Cl

2,4-Dichloropyrimidine

N

N

Cl

B OHHO

O O

INT-C

N

N O N

O

O

NHMetathesis

Suzuku Rection N

N

Cl

O

INT-C

Br

O-Alkylation

Reduction N-Alkylation

Reduction

Reduction Bezylic O-Allylation

4N HCl


N,O,O-Macro Cyclic CompoundsN,O,O-Macro Cyclic CompoundsN,O,O-Macro Cyclic-Non-RCM Route

CHOOH

O2N

Cl Cl

CHOO

O2N

Cl O

O2N

Cl

HOBr Br O

O2N

Cl

OBr

N

N

Cl

O

NO2

Cl

O

O

NH

5-Nitro Salicylaldehyde

pyrrolidine

N

N O Cl

O

O

NH

N

N

Cl

OH

N

N O N

O

O

NH

INT-B

1 2 3

4 5 Target

Reduction O-Allylation

O-AllylationCoupling Reaction

INT-A

N

N

Cl

Cl

2,4-Dichloropyrimidine N

N

Cl

B OHHO

OO

Suzuku Rection Reduction

INT-B

N-Alkylation

Reduction


A Potent Inhibitor of Cyclin Dependant Kinases (CDKs), Janus A Potent Inhibitor of Cyclin Dependant Kinases (CDKs), Janus Kinase 2 (JAK2) and Fms-LikeTyrosine Kinase-3 (FLT3) Kinase 2 (JAK2) and Fms-LikeTyrosine Kinase-3 (FLT3)

N,N,O- Macro Cyclic RCM Route

30

CHO

O2NO2N

N

5-Nitro-Benzaldehyde

N

N

Cl

Cl

2,4DichloropyrimidineN

N

Cl

BOHHO

OH OH

N

N

Cl

Br

1 2

O

NH

H2N

N

3

INT-A

INT-B

N

N

N

NH

O

N

N

N

NH

O

INT-B

Metathesis

Suzuku Rection coupling ReactionO-Alkylation

NO2- Reduction

Reductive amination


1,2,3,4 tetra hydro quinoline Derivativies1,2,3,4 tetra hydro quinoline Derivativies

N NH

(Z)

N

(Z)

Quinoline BocNBoc

OHBr

NBoc

O

NBoc

OHHN

R1

R1NH2R2X

NBoc

OHN

R1

Dry HClR2

NH

OHN

R1

R2

N

OHN

R1

R2R3 OH

O

R3O

MitsunobuCenter Inversion

NBoc

HNR1

OH R2X

NBoc

OHN

R1

Dry HClR2

NH

OHN

R1

R2

N

OHN

R1

R2R3 OH

O

R3O

Anti

Syn

1 2 3 4

5 6 7

8 9 10

Reduction N-Boc Bromo-Hydrine Epoxidatioin

Opeing of Epoxide O-Alkylation De-Boc Amidation

O-Alkylation De-Boc Amidation


Asymmetric Aldol Products -Chiral Oxazolidinone AuxiliaryAsymmetric Aldol Products -Chiral Oxazolidinone Auxiliary

EXAMPLES

Tetrahedron. 1992, 48, 2132- 2142 J.Org.Chem. 1990, 55, 6260- 6268

32

ChiralNHO

O

NO

O1. BuLi

2.n-BuCOCl

O1. n-Bu2BOTf/ TEA

2.R-CHONO

O O

R

OH

HO

O

R

OHLiOH/ H2O2

THF/ H2O

1 2

TARGET

Aldol Reaction

David A. Evans(S)-4-benzyloxazolidin-2-one

Evans- SYN

O

BO

n-Bu

n-Bu

n-Bu

R

HN

OO

SYN

HO

O OHHO

O OH

HO

O OH

HO

O OH

NHO

O OH

N

BrBr

Br

HO

O OH

N

HO

O OHHO

O OHHO

O OH

HO

O OH

HO

O OH

HO

O OHHO

O OH


Pyrrolidine Derivativies- Azamethine Ylide

33

NH

MeO2CGlycine

Para-HCHO

PhMe/ RefluxBn-Br/ 0 oCCO2Me

O

O

OOBn

O

O

O

2.Pd/C/ EtOAc

1.Boc2O/ TEA DPPA/TEA

BnOH/C6H6 N

Ph

N

MeO2C NHCbz

NPh O

NPh

N

NHCbz

1. LiOH/THF

2. SOCl2/Pyrrolidine

ON

MeOHPd(OH)2

NPh

N

NH2O

N

1 2 3

4 5 6

7

TARGET

NaOMe, DMFO

O

OMeOBn

I2, xylene

Reflux

Maleic anhydride Azomethine-ylide

Curtius Rearrangement & Insitu Cbz Protection

N

MeO2CO

OH

BocN

MeO2C NHCbz

Boc

1.De-Boc

Reductive amination

NPh OBr

HN OPd(TPP)4

Buchwald Coupling

De-Bn lation

Cbz- De Protection

Regio Specific addition


Biological Active cyclopetanone-3-amine Derivatives

Bn-Br/ 0 oC OOBn

O

O

O

Pd/C/ EtOAc

2.NaN3/H2O/Bu4NBr

1. LiOH/THF

2. SOCl2/PyrrolidineMeOH

Pd(OH)2

1 2 3

4 5

6

NaOMe, DMFO

O

OMeOBn

KMnO4/H2O

Curtius Rearrangement

O

O

OMeOBn

HO2CHO2C O

Ac2O/NaOAc

130 oC/ 5h

OO

NH

O

O

O1.(COCl)2/DMF

BnOH

Cbz

OOH

O

OO

NH

O

ON

Cbz

NH2

O

ON

ON3

O

OO

N CO

OO

O

BnO

Claisen condensation


N

O

N

NHO

BocN

NHO

Boc

BrBr

N

NHO

Boc

N3

N

NHO

Boc

H2N

N

NHO

Boc

NSO

O

Cl

MeO2C

HN

NHO

NSO

O

Cl

MeO2C

HCl

N

NHO

Boc

HNS

OO

Cl

NH2OH.HCl/NaHCO3

N

NHO

Boc

Br

BocN

N

Boc

OH

EtOHPTS-Cl

NaOH/Acetone

BeckmannOxime

Br2/PCl5 H2, Pd/C

NaN3/DMF H2, Pd/C

SO

OClCl

TEA/DCM

MeO2C

Br

KOtBu/DMF

HCl/ Et2O

1,4-diazepane-Derivativies


Indanone Derivatives

36

R1

CHO

R2

R1

R2

OEt

O R1

R2

OEt

O

O

R1

R2

Cinnamate

OH

R1

R2

R1

R2

R1

R2 O

R1

R2O

Indane-1-one

Ph3POEt

O

Wittig Reaction

H2, Pd/C

EtOH

1.LiOH/THF:H2O

2. SOCl2/CS2/AlCl3Friedel–Crafts

NaBH4

THF/MeOH

cat. CSAC6H6/ reflux

mCPBA/DCMNaHCO3

InCl3/THF

R1 = Cl, Br & FR2 = H, Cl, Br & F

THF

CHOOEt

O

OEt

O

O

Cinnamate Indane-1-one

Ph3POEt

O

Wittig Reaction

H2, Pd/C

EtOH

1.LiOH/THF:H2O

2. SOCl2/CS2/AlCl3Friedel–Crafts

R1 = Cl, Br & FR2 = Cl, Cl & F

THF

R2

R1

R2

R1 R1

R2

R1

R2

R1

R2

R1

R2

O

H2N O

O

iPrOH/ reflux

S+

I- NaH HNO

O

OHR2

R1

HNOH

O

OHLiOH/THF:H2O

Indane-2-one

2,4- Sub

3,5- Sub


Subs of (4-Nitro-1H-imidazol-1-yl)pyrrolidin-2-oneSubs of (4-Nitro-1H-imidazol-1-yl)pyrrolidin-2-one

EXAMPLES

N

O

N

N

O2N

N

O

N

N

O2N

N

O

N

N

O2N

O

N

O

N

N

O2N

OH

N

O

N

N

O2N

N

O

N

N

O2N

N

O

N

N

O2N

N

O

N

N

O2N

Cl F

FF

F

Cl

Cl

Cl

J. Med. Chem. 2002, 45, 1184- 1194 J.Org.Chem. 1989, 54, 6069- 6100

37

O OBr

BrBr

ORed PBr2

RNH2 Br

BrNHR

O

TEA/THF

NaH/THF

NR

O

Br

N

NH

O2N

K2CO3 / DMF NR

O

NN

NO2

1 2 3 TARGET

Br

BrOMe

O

MeOH

K2CO3/Toluene

n-Bu4NHSO4 Br

MeOO

N

NH

O2N

K2CO3 / DMFEt3NBnBr

OMe

O

N

N

NO2


N

N N

Cl

H2N

NO

R

X N

N N

NCl

H2N

R

N

N N

Cl

H2N

R

N

N N

Cl

H2N

R

OHN

N N

Cl

H2N

R

OH

N

N N

Cl

H2N

NO

F

N

O

N

N N

N

H2N

Cl

N

NN

N

N NH2N

Cl

N

O

N

N N

Cl

H2N O

NHNN

OH

N

N NH2N

Cl

N

O

OH

Heat Shock Protein-90 Inhibitors

e-mail: [email protected] www.Laxmi GenChem.com 38

Heat Shock Protein InhibitorHeat Shock Protein Inhibitor

39

DiBAL-H

SOCl2 scaffold NN N

OTBDMSCl

OO

H2N

Br2

Br

DMF

1 23 4

NN N

OHCl

OO

H2NBr

TBAF/THF

NaH

5

O

O

O

HO n-BuLi

MeI / THF

6

SOCl2MeOH THFAcOH

Target

O

O

O

HO O

O

O

O O

O

O

O

Br

O

OHO

Br

O

OCl

BrCHCl3

N

N N

Cl

H2NPMB

OH

N

N NH

Cl

H2N

OH

NN N

Cl

H2NPMB

OMeO

N

N N

Cl

H2N

I

PMB

N

N NH

Cl

H2N

I

1 2 3

TFA / H2SO4

80 0C/ 2h

Pd(PPh3)4

Binap TEA

100 Psi

L-selectride

K2CO3 / DMF MeOH

PMB-Cl

N

N NH

Cl

H2N

OTBDMSTBDMS-Cl

IMD

80 0C

scaffold4

Carbonylaation


Heat Shock Protein InhibitorHeat Shock Protein Inhibitor

40

O

O

O

O

HO H+

MeOH

O

AcOH

HNO3 Pd / C

NaNO2

HCl

1

O

O

O NO2

O

OO

NH2

O

OO NH

NO2

O

O

O NH2NO2 Pd/C

EtOAcO

O

ONH

NN

O

OHNH

NN

DiBAL-H

2 3 4

56 7 8 9

N

N N

Cl

H2N

O

NH

NN

OH

OMe

O

O NHO

TFAKNO3

Ac-Cl

Et3NEtOAc

O

O

OO

NH2NH2

Con.-HCl

11

O

ClNH

NNN

N NH

Cl

H2N

OTBDMS

N

N N

Cl

H2N

O

NH

NN

OTBDMS

TBAF

THFNaH

SOCl2CHCl3

10 Target


41

Heat Shock Protein InhibitorHeat Shock Protein InhibitorPd(dppf)Cl2bis(pinacolato)diboronKOAc, dioxane/ 800CK2CO3 N

N NH2N

Cl

N

O

FF

BocN

O

HN

NBoc

N

N NH2N

Cl

N

O

FF

ONH

HO HOTEA DCM / TEA

BocN

MsOK2CO3, DMF

F

F

OHBr

TFA

(Boc)2O Ms-Cl

N

N NH2N

Cl

N

O

I

N

N NHH2N

Cl I

K2CO3, DMF

N

O

Br

F FO

Br

NBoc

F FO

Br

NH

F FO

Br

NAcOH/ CH2ONaBH(OAc)3 TFA

SuzukiINT-A

INT-B

INT-B

N

N NH2N

Cl

N

O

FF

ON

Pd(dppf)Cl2bis(pinacolato)diboronKOAc, dioxane/ 600CK2CO3

F FO

Br

N

SuzukiINT-A

N

N NH2N

Cl

N

O

I

N-Methylation

Reductive Aminaation


Biological Active Hetero Cyclic Ring CompoundsBiological Active Hetero Cyclic Ring Compounds

42

NS

HN

F3CO

OEt

5M KOH, MeOH, Reflux NS

HN

F3CO

OH

NMeO

H.HCl

EDCI/DIPEA/DMF

NS

HN

F3CO

N OMe

CH3MgBrN

S

HN

F3CO

NH2OH.HCl, Py, MeOH

NS

HN

F3CH2N

NCS

F3C

NH4OH

Dioxane

HN

F3C

NH2

S

O

Cl+

O

H

OEt

NS

HN

F3CNOH

Zn-AcOH

EtOH/ Reflux

THF/ 0 oC to RT

weinreb amide Ketone OximeGrignard Scafold

N

S

HN

HN

NN

N

O

O

EDCI / HOBT/ DMF

OH

N

S

HN

HN

NN

N

O

HN

O

N

S NH

K2CO3/ DMF80 oC/ 1h.

O

NN

N

O

1

O

N

S

HN

HN

NN

N

O

O

O

6

BrO

OO

OH

NN

N

O

O

OLiOH

THF/H2O

MeNH2

EDCI / HOBT/ DMF

HClFFF

F FF

F FF

F FFNH2

N

NH

OH

NH2

O

CH2O,HCl

H2O NHN

NH

OH

OSOCl2,MeOH

NHN

NH

OMe

OSeO2,PPSE

NN

NH

OMe

O

NEt3, CCl4

Base Hydrolysis

t-Butyl ester is intact

Acid Hydrolysis

2 3 4

7

5

isothiocyanate Thio Urea thiazole

Scafold


Biological Active Hetero Cyclic Ring CompoundsBiological Active Hetero Cyclic Ring Compounds

43

N NO2

BrBr THF NO2N

HN Br Fe, AcOH CH(OEt)3, HCl

DMF/H2O

CO, Pd(BINAP)Cl2

Hunig's base, n-BuOH

LiOH

THF/H2O

NH2N

HN BrNN

N Br

NN

N CO2Bu

NN

N CO2H

NS

HN

CF3HN

NN

N

O

1.TFA/DCM

EDCI/HOBT

6

1 2 3 4

5

NBoc

NH2

N N N N

NNBoc

Boc Boc Boc Boc

Boc NS

HN

CF3HN

NN

N

O

N

2. NaCNBH3

AcOH/CH3CHO

Scafold

Carbonylation

Reductive amination


44

OHH2N

R1

O

OH2N

R1

O

(S)-Alanine

OHN

R1

O

Boc NH

HN

R1

ONH2Boc

R2 O

NHNN

NH

HN

R1

R2Boc

NN

N

HN

R1

R2Boc

NN

NNH2

R1

R2

1 2 3

4 5 TARGET

Esterification N-Boc Hydrazide

N-Methylation De-BocCyclization

Acid Hydrazide

R1= H, CH3Ph, CH (CH3)2

R2= Me, PhR2 O

NHDry HClMeOHR-CN

Pinner reaction

MeI Dry HCl

4-ME, 3, 5-DI Substitutes- 4H-1, 2, 4-triazols


API Projects


ZudovidineZudovidine Chemical Name is Chemical Name is 3 azido-3 -deoxythymidin(AZ′ ′3 azido-3 -deoxythymidin(AZ′ ′ T).T). DNA intercalating drug type.DNA intercalating drug type. Retrovir activityRetrovir activity..

HN

NO

HO

O

OHN

NO

TrtO

O

OHN

NO

TrtO

O

O

OH OH OMes

HN

NO

TrtO

O

O

HN

NO

TrtO

O

O

N3

HN

NO

HO

O

O

N3

AZT4

1 2 3THYMIDINE

NaN3/Li2CO3

t-BuOk

DMF

DMSO


StavudineStavudine Chemical Name is Chemical Name is 2',3'-didehydro-3'-2',3'-didehydro-3'-

deoxythymidinedeoxythymidine.BRAND Name is .BRAND Name is ZeritZerit StavudineStavudine is converted within the body to its active is converted within the body to its active formform

((stavudine triphosphatestavudine triphosphate). This active form is similar to ). This active form is similar to thymidine triphosphatethymidine triphosphate, a chemical that is required by the , a chemical that is required by the HIV virus to make new DNA.HIV virus to make new DNA.HN

NO

HO

O

O

OH

HN

NO

MesO

O

O

OMes

HN

NO

HO

O

O

HN

NO

HO

O

O

THYMIDINE 1

STAVUDINE

HN

NO

O

O

O

Oxtane INT

Crude STAVUDINE

Mes-Cl/NMM

O

Aq-NaOH

75 oC/ 3h30 oC/ 1h

Alcholic KOH NMPO / Acetone

60 oC/ 3hIPA 75 oC/ 3h


48

OHOHO

HO OH

OOHO

O O

CH3OOTsO

O O

CH3

OH3C O

O O

CH3OHH3C O

HO OH

OAcH3C O

AcO OAc

N

NFNH2

O

H3C O

AcO OAc

NH

NF

NH2

O

Acetone/MeOH

H2SO4/CH2Cl2/TEA

CH2Cl2/PTS-ClPy/DMAP

NaBH4/DMSO H2SO4/H2O

CH2Cl2/Py/AC2O 1.HMDS/MeSO2Cl/TOLUENE

2.SnCl4/CH2Cl2

H3C O

AcO O

O

anchimeric assistance

N

NF

NH

O

TMS

TMS

Up side attack

Capiceitabine

N

NFNH

O

H3C O

AcO OAc

O

O

n-amyl chloroformate

Py/DCM N

NFNH

O

H3C O

HO OH

O

O

DCM TOLUENE

NaOH/H2O/MeOH

D-ribose

Cytosine

Capiceitabine (Anti-Tumor drug/ Xeloda Trade Name)


49

NH

(R)O

O

O

Boc

NH

(R)OH

O

HO

BocH2N (R)OH

O

HO

NH

(R)OH

O

O

Boc

H2N

Isobutyl chloroformate

NMM/DCMBoc2O/NaOH

H2O

DMS

NH

(R)HN

O

O

Boc

O

O

OCl

Mixed anhydride

O

H2N (R)HN

O

O

HN (R)HN

O

O

O

AcOH/Ac2OHCl/H2O

L-Serine

Lacosamide

NaOH/H2O

Lacosamide (Anticonvulsant / Vimpat Trade Name)


50

NCl

CHOOHCAc2O

NClCHO

NCl

OHMgBr

I

O

O

Pd(OAc)2

NCl

O

O

O

NCl

OH

O

O

(-)-B-Chlorodiispopinocamphenyl borane

.H2O

NCl

OH

OHMeMgCl/CeCl3 NCl

OH

OMes

THF

Mes-Cl/DIPEA

ACN/Toulene

NCl

HO

S

O OH

NCl

HO

S

O ONa

HS

O OH

NaOMe/DMSO

TBA salt

1.AcOH/Toulene

2.NaOH/MeOH

H2N

NH2

DIPEA/DCM

Montelukast Sodium

Montelukast Na (leukotriene receptor antagonist / Singulair Trade Name)



Vardenafil-INT

Vardenafil is a PDE5 inhibitor used for treating erectile dysfunctionVardenafil is a PDE5 inhibitor used for treating erectile dysfunctionO

NH2

O OCN

O

NH2

NH O

NH

NHNH2N2H4.H2O

IPA

O

N

HNN

NH

OO

O

N

HNN

N

O

O

NH

O

O

O

Verdanafil-Int

O

NH

O

O

OOH

O

NH

O

OH

O

NH2

O

Cl

INT-3

INT-3

O

N

HNN

N

O

SN

OO

N

Vardenafil


NH2

OO

NH2

OO

HCl HClN

OO

OON

OO

OO

NH2

OO

NH2

OHO

NH2

OO

HCl

Pt-C/MeOHIPA/tBuOKToluene/TEA

CAS No.: 61367-07-5Ref : Organic Process Research & Development 2009, 13, 1141–1144

Trans-4-Amino-1-cyclohexanecarboxylic Acid HClTrans-4-Amino-1-cyclohexanecarboxylic Acid HCl


Methyl trans-3-amino-cyclobutane HCl

HO2CCO2H

SO2Cl2

HO2CCO2H

ClPy/

CO2H

ClSO2Cl2/MeOH

CO2Me

Cl

NaN3

CO2Me

N3

CO2Me

N3

CO2Me

H2N

CO2Me

H2N

Pd-C/H2

Pd-C/H2

76%64%

81%

32%

29%

67%

71%

CAS 74316-29-3

Ref:Synthetic Communications1, 41: 1644–1649, 2011


(Toluene-4-sulfonylmethyl)-phosphonic acid diethyl ester

SCH3

CH3

NCS

S

CH3

ClP(OEt)3

S

CH3

PO OEt

OEt

H2O2 / Na2WO4

CH3

PO OEt

OEt

OSO

1-Methyl-4-methylsulfanyl-benzene 1 2 3Mol. Wt.: 306.32


1,1-difluoroethanesulfinate (Hu'S Reagent) Derivatives

N SH

EtO P CF2BrO

OEt

KOH/ H2O/MeCNN S CF2H

NaIO4/RuCl3.H2O (cat)N S

CF2H

O O

2-(Difluoromethylsulfonyl)pyridineHu'S Reagent

2-Mercaptopyridine

ClN SO

OF F

ClI

ClSO

F FNaO

Br

Br

N SO

OF F

Br

SO

F FNaO

Br

BrN S

O

OF F

SO

F FNaO

Br

BrBr

N SO

OF F

SO

F FNaO

Br

78%

Br

Br Br

70%

N SCF2H

O O


Perampanel –INT (1-Phenyl-5-(pyridin-2-yl)-2(1H)-pyridone)

N

O

(HO)2BN

O

N

NH

O

N

Suzuki Coupling

N BrN

O

BrN

Br

Br

De-Methylation

Methylation

N

O

N

B(OH)2

Exact Mass: 122.05

INT-1 INT-2INT-3

INT-4 CAS No: 381725-50-4

N

O

N

CN

Perampanel


HO O

O

NH2

HO O

O

NHBocHO OH

O

NH2

H2SO4/MeOH NaHCO3/(BOC)2

1,4-DiOxaneTBDPSO O

O

NHBoc

TBDPS-Cl

Imidazole/DMF

TBDPSO

O

NHBoc

DIBAL-H

DCM; - 78 oCTBDPSO

NHBoc

HN

OH

NH

PhHO

DCM/MgSO4~ 65 oC for 3 steps

N PhHO

OH

OBn

OBn

TBDPSONHBoc

N PhHO

OBn

TBDPSONHBoc

HN PhZn, Cu(OAc)2

AcOH; 60 oC92%

OBn

TBDPSONH

N NHBocBn1) TFA/DCM

2) HgO

NHBoc

NHBocS

BocHN

NBoc

NBoc

OBn

iPrMgCl / THF; - 78 oC86%

HN N O

NBocN

OBocN

NBoc

TBDPSO

Bn

OBn

1 2 3 4

5 6 7

8 9 10

13 14

12

14

CHO

11

Tetrahedron: Asymmetry 9 (1998) 629–646

J. Am. Chem. Soc. 2011, 133, 20172–20174- Comp-2Tetrahedron: Asymmetry 1997, 8, 2381–2401Tetrahedron: Asymmetry 9 (1998) 629–646.

J.CHEM. SOC. CHEM.COMMUN., 1989

J. Am. Chem. Soc. 2011, 133, 20172–20174- Comp-2

N PhHOShiff's Base Reductive Amination

NaH/BnBr

THF; 0 oC93%

Site One Ref erence

NH2OH. HCl/MeOH86%

NaBH4/MeOH87%

AgOACThen I2;AgOAc

Then AcOH,AgOAC

3 Step One Pot Cyclization

Saxitoxin-Natural Product. ( Total 19 Steps)


O

HO

HO O

F

O

BzO

BzO N

F

NHPO

OO

O

O

NMI, DCM, 0 oC to rt 1h, 52%

CHOO

O

Ph3PC(Me)CO2Et, DCM, -40 oC, 79% E\Z 97:3

O

OCO2Et

O

OOHHO

HCO2Et

O

OCO2Et

ROH

F

O

BzO

BzO O

F

O

BzO

BzO

F

OAc N

O

NHBz

O

BzO

BzO N

F

NH

O

O

O

HO

HO N

F

NH

O

O

O

OO

OH

CO2Et

SO

O

KMnO4, acetone0 oC, 87%

1.SOCl2, TEA, DCM, -0 oC,2.aq. NaOCl, TEMPO, NaHCO3, MeCN, 0 oC,

1.TEAF, dioxane 100 oC, 87%2. (MeO)2CMe2, Con.HCl,dioxane, rt, 87%

R=SO3HR=H

Con.HCl, EtOH, rt

BzCl, pyridine,rt

1.Li(O-tBu)3AlH, THF -20 oC2.AC2O, DMAP ,-20 oC

SnCl4,PhCl ,65C70% Aq. AcOH,100 oC

25% methanolic ammonia, 0-15 oC O

F

OPN

H

OO

O N NH

O

O

OPh

NN

NHBz

OTMS

D(+)-Glyceraldehyde CAS : 453-17-8

CAS :5736-03-8

F

FF

FF

Sofosbuvir Synthesis


CytidineCAS:65-46-3

O

O

O NN

O

NHBz

OH

SPDIT

O

HO

HO NN

O

NH2

OH

O

O

O NN

O

NHBz

O

O

O

O NN

O

NHBz

SPDIT OHO

BzO

BzO NN

O

NHBz

OH

O

BzO

BzO NN

O

NHBz

OH

O

BzO

BzO NN

O

NHBz

F

O

BzO

BzO NN

O

NHBz

O

BzO

BzO NNH

O

F

O

O

HO

HO NNH

O

F

O

NH

P OOO

O

ClO

HO

O NNH

O

F

O

PNH

OO

O

1.Bz2O,DMF, rt2.TIDPSCl2, DMF

1.DMSO, TFAA, TEA, -15 oC

1.TBAF, AcOH,rt, 61%2.BzCl, pyridine, rt, 67%

DAST, toluene, -20 oC-rtMeLi, -78 oC

80% AcOH, reflux, 91%

NH3, MeOH, rt, 60%

NMI, THF, 0 oC-rt,1h, 15% SOFOSBUVIR

SPDIT

19%14% 15%

OPh

12 3

4 5

6a 6b 6c7

8

9

Sofosbuvir Alternative ROS


O

HO

HOO

NH

HN

O

O

F O

HO

HO NNH

O

O

F

O

HO

OP

O

HN

O

OO

NNH

O

O

F

OP

O

HN

O

OO

F

F z

F

F

t-BuMgCl/THF

PL-102

PL- 102 ( IsoSteric Structure to Sofosbuvir)


N

HN NH

N

N

N FF H

O

HN O

O

ONHO

O

N

HN N

H

O

HN O

OB

O

O

N

HN N

H

OOBO

O

HN

N

N FF

O O

Br

NH2

NH2

BrN

H

OO

O

O

NH2

O

OO

OH

O

O

N

FFO O Br

O

ON

O O

OK O

FF

Br

Cl

LDP-IMP-4

ONHO

O

HO Br

Ledipasvir-IMP-4 Synthesis ( Total 24 Steps)


ADU-S100 Synthesis ( Total 21 Steps)

OHHO

HOO

N

NNH2

N

N

OBzBzO

BzOO

N

NNHBz

N

NPyridinePhCOCl

2N NaOH

OHHO

HOO

N

NNHBz

N

N

DMTr-Cl

Pyridine

ODMTrHO

HOO

N

NNHBz

N

N

1 2 3 4

ClP

N

O

N

ODMTrHO

TBDMSOO

N

NNHBz

N

N

ODMTrTBDMSO

HOO

N

NNHBz

N

NTBDMS-ClPyridine

5 5a

Et3N, DCM

+ ODMTr

HOH

OTBDMSO

NN

N

NHBzN

PO

NNC

6

3'

3'2'

ODMTr

HO H

OTBDMSO

NN

N

NHBzN

POH

A) Pyridiium trifluoroacetate

B) tert-butylamine3'

C) dichloroacetic acid in DCMOH

HO H

OTBDMSO

NN

N

NHBzN

P OHOH

3'

7 8

5'O-DMTr Deprotection

O-CE De-Protection

Elimination

O-Bz Deprotection1'-OH- Protection

OH

N & O-Bz Protection



ODMTrTBDMSO

HOO

N

NNHBz

N

N

5a

2'

ClP

N

O

N

Et3N, DCM ODMTrOTBDMS

OO

N

NNHBz

N

N

2'PO

NNC

6a



OH

HO H

OTBDMSO

NN

N

NHBzN

P OHOH

3'

8

ODMTrOTBDMS

OO

N

NNHBz

N

N

PO

NNC

D) ACN/Py ODMTr

TBDMSO

O

O

NN

NHBzN

N

PO2'

2'

O

HO H

OTBDMSO

NN

N

BzHNN

P OHOH

NC

O3'

5' & 2'- Linking

ODMTr

TBDMSO

O

O

NN

NHBzN

N

PO

O

HO H

OTBDMSO

NN

N

BzHNN

P SHOH

NC

S3'

P-S Insertion

2'E) DDTT

OHTBDMSO

O

O

NN

NHBzN

N

PO

O

HO H

OTBDMSO

NN

N

BzHNN

P OHSH

SF) DCA/Water 3'2'

G) DMOCP

CN

O-DMTr DeprotectionH) I2 / H2O

O

OTBDMSO

O NN

NHBz

NN

POH

OH

O

TBDMSO

NN

N

BzHN N

PHS

SO

O5' & 3'- Back Linking

I) SiO2

J) NH4OH, MeOH

O

OTBDMSO

O NN

NH2

NN

POH

OH

O

TBDMSO

NN

N

H2N N

PHS

OSH

O

O-CE & N-Bz Deprotection

L)TEA-3HF,

O

OHO

O NN

NH2

NN

PO

H

OH

O

HO

NN

N

H2N N

PHS

O

SH

OO-TDDMS Deprotection

9 10

11 12

13 ADU-S100M) SepPak desalting N)Ion exchange

K) Prep.HPLC

CN

Medicinal ChemistryVijay M Reddy 65

NC

O

NNN N

N N

SMeO

OClNC

O

NH2HN

N

SMe

MeOOC

N N

SMeO

OCl

NHH2N

OO O

N N

N N

SMeO

OCl

HOOC

NC

COOMe

N N

SMeO

OCl

Cl

N

SMeO

OMeOOCN

Br

MeOOCN

Br

HOOC

ClNH2

MeOHSOCl23 h87%

THFNaSMe

reflux16 h57%

m-CPBA

DCM20 C16 h77%

AlMe390 C2 h87 %

PCl5

benzenereflux16 h

NH2NH2H2O92% Toluene

reflux3 h96%

1. Oxalyl Chloride2. PCl5, CBr4, DCM

1 2 3 4

6 7 8

9

10Et3N

HN N

SMeO

OCl

O5

NC

O

NH2HN

9

NH2.NH2.H2O;

16 h; 20 C; 80%

Synthesis of G007-LK-Tankyrase 1/2 Inhibitor

Ref: J. Med. Chem. 2013, 56, 3012−3023

Research Work


R & NH are at - Position

R & NH are at Position

R is at - NH is at Position

- Amino acid

- Amino acid

- Amino acid

NO

HR

H OH

N

OH

RH OH

N

OH

H

R

OH

NN

NN

O

O

O

O

R

R

R

R

- PolyPeptide chaine

N N N

O O O

RRR

H

H

H

H

H HH


N N N

O O O

H HH


R R R

Types of Amino Acid & Poly Types of Amino Acid & Poly peptidepeptide

Vijay M Reddy Medicinal Chemistry 67

Peptide-based nano structuresPeptide-based nano structures

68Vijay M Reddy Medicinal Chemistry

Choice of Backbone Structure

1972 Hassel predicted that cyclic tetra peptides composed by alternative α and β- amino acids would stack through backbone- backbone H-bonding to form hollow cylindrical structure.

Later X-ray crystallographic work partially validated these prediction. Two of four expected inter subunit H-bonding was observed.

1974 De Santis and co workers recognized the possibility of forming cylindrical structure by ring –stacking of cyclic D,L- α- peptides.

Early attempts to experimentally verify this prediction met with limited success due to the extreme insolubility of peptides examined.

1993 Ghadiri and co workers complied 1st evidence of forming hollow tubular structure by self -assembly of cyclic D,L- α- peptides, by bearing suitable hydrophobic side chain.

Molecular modeling and experimental studies indicated that 8 –residue cyclic peptides possess optimum balance of low ring-strain .Ghadiri, M. R et al. Nature 1994, 369,301- 304.Ghadiri, M. R et al. J. Am. Chem. Soc. 1998, 120, 651- 656.Ghadiri, M. R et al. J. Am. Chem. Soc. 1996, 118, 43-50.


Choice of Backbone Structure

Cyclic D,L- α- peptides with 8, 10 and 12-residue which give internal Van der waals diameters 7, 10, 13 Å respectively.

1996 Dieter Seebach reported that cyclic tetramers of β3- amino acids can adopt flat ring confirmation and stack in the solid state through back- back bone H-bonding.

Ghadiri, M. R et al. J. Am. Chem. Soc. 1998, 120, 651- 656.Seebach, et al. HelV. Chim. Acta 1997, 80, 173-182

(a) flat-ring C2 symmetrical conformation described by Seebach

(b) an alternative flat-ring C4 symmetrical conformation.central hole 2.6-2.7Å in diameter, large enough to allow passage of water and small ions


A Model A Model CycloCyclo Peptide Nano tubes Peptide Nano tubes

NH

NHO

R

OR

HN

HNO

R

OR H H

HH

HH

HH

3- Cyclic Peptide (Tetra peptide)

HN

HN

HN NH

NH

NH

NH

HN

O

O

O

OO

O

O

O

RR

R

RR

R

R

R

- Cyclic Peptide (Octa Peptide)

D

D

D

D

L

L L

L

In β3-Tetra peptides CH2- Group α to Carbonyl group is responsible for optimum balance of Cyclo Peptides.


- Peptide Nano tube (Octa Peptide)

N

NN

N

N

NO

OO

O

O

O

R

H H

HH

H

HN

ON

O

R

H

H

N

NN

N

N

NO

OO

O

O

O

RH H

HH

H

HN

ON

O

R

H

H

N

NN

N

N

NO

OO

O

O

O

R

H H

HH

H

HN

ON

O

R

H

H

N

NN

N

N

NO

OO

O

O

O

RH H

HH

H

HN

ON

O

R

H

H

N NN N

OO OO

R R

H H H H

N NN N

OO OO

R R

H H H H

N NN N

OO OO

R R

H H H H

N NN N

OO OO

R R

H H H H

- Peptide Nano tube (Tetra peptide)

Structural attribute of Cyclic Peptide

Ghadiri, M. R et al. J. Am. Chem. Soc. 1998, 120, 651- 656.

No N

et Dipole M

oment

- Octa Peptide Nano tube

N

NN

N

N

NO

OO

O

O

O

R

H H

HH

H

HN

ON

O

R

H

H

N

NN

N

N

NO

OO

O

O

O

RH H

HH

H

HN

ON

O

R

H

H

N

NN

N

N

NO

OO

O

O

O

R

H H

HH

H

HN

ON

O

R

H

H

N

NN

N

N

NO

OO

O

O

O

RH H

HH

H

HN

ON

O

R

H

H

N NN N

OO OO

R R

H H H H

N NN N

OO OO

R R

H H H H

N NN N

OO OO

R R

H H H H

N NN N

OO OO

R R

H H H H


Ghadiri’s α-cyclic polypeptides


Some other cyclic polypeptide


Jan H. van Maarseveen et al.Org. Lett., Vol. 8, No. 5, 2006, 919-922

Tyrosinase inhibitor- Click Chemistry ApproachN

O

NHN

HO

HNO

O

N

O

NN

HO

HNO

O

NN

N

O

NN

NHO

O

NN

N

O

NN

HO

N

O

NN

O

Cyclo- [Pro-Val-Pro-Tyr]

HO

NN

Triazole analogue 2

Pro

Pro Val

TyrTyr Pro

ValPro

Pro

Pro

ValVal

TyrTyr Pro

Triazole analogue 3 Triazole analogue 4

Pro

Cyclo- [Pro-Val-Pro-Tyr] is a natural product isolated from Lactobacillus helveticus.

Tyrosinase (phenol oxidase) [EC 1.14.18.11 is known to be a key enzyme for melanin biosynthesis in plants, microorganisms and mammalian cells, and also known to be as a copper-containing enzyme.

Compound Tyrosinase activity IC50/mMa

cyclo-[Pro-Tyr-Pro-Val]

1.5

Triazole analogue 2

0.5

Triazole analogue 3

0.6

Triazole analogue 4

1.6

(S) N(S)

O

NHN

(S)

HO

(S)

HNO

O

O

Cyclo- [Pro-Val-Pro-Tyr]

Pro

Pro Val

Tyr

R'

NN

N R

R'

1,3- Cyclo addition

Alkyne

Azide

1,4- Di substituted1,2,3- Triazole

RN

NN

Catalyst

123


Reasons behind the Replacement Reasons behind the Replacement of Peptide Bond with Hetero of Peptide Bond with Hetero

CyclicCyclic

Triazole & Oxadiazoles mimics planarity of amide bond.Triazole & Oxadiazoles mimics planarity of amide bond.

Triazole and peptide bond both possess large dipole (5D, 3.7D, respectively).Triazole and peptide bond both possess large dipole (5D, 3.7D, respectively).

CC distance distance of of Peptide and Triazole Peptide and Triazole & & Cβ distance Cβ distance of of triazole and oxadiazole triazole and oxadiazole are are comparable.comparable.

Peptide bond Hetero cyclic are Peptide bond Hetero cyclic are Isoteric Structures.Isoteric Structures.

Jan H. van Maarseveen et al.Org. Lett., Vol. 8, No. 5, 2006, 919-922Kolb, H.C., Sharpless, B.K. Drug. Disc. Today. 2003, 8, 1128-1136.Kevin Burges, J. AM. CHEM. SOC. 2011, 133, 462–477

H2N

R1

NNN

OHR

O

5.1 Ao

NH2

OR1 N

H

ROH

O

3.9 Ao

Peptide Bond 1,2,3- Triazole

SP3 N N

O

H2N NH

R2

O

5.2 Ao

1,2,4- Oxadiazole

H2NNNN

OHO

5.5 Ao

1,2,3- Triazole

R1 R2

R1

C CDistance C CDistance C CDistance


N N

O(S)

NH(S)

R2HN

O

NN

O (S)HN

(S)

R2 NH

O

R1

R1

NN

O

(S)

HNR1

(S)

R2

HN

O

NN

O(S) N

HR1

(S)R2 HN

O NN

O

(S)NH

R1

(S)

R2

NH

O

N NO

(S)

HN

R1

(S)R2

NH

O

HH

H

H

HH

HH

C2C4

N N

O(S)NH

(S)R2HN

OPg1

R1

Pg2

CC22 & C & C44 Symmetry 1,3,4- Oxadiazole Back Bone Cyclic Peptides Symmetry 1,3,4- Oxadiazole Back Bone Cyclic Peptides

Monomer consist of 2-Amino acids with 1,3,4-Oxadiazole


Chemistry Scheme Execution

OHO

H2NR1

OO

H2NR1

OOH

NR1

Boc NH

OHN

R1

Boc NH2

SOCl2/MeOH

reflux; 6h;

(Boc)2O/TEA

DCM, RTOver night

HyrazinehydrateMeOH/ Reflux4h

OHO

Cl

N NNN

O

N NO

ClNH

OHNBoc NH2

NH

OHN

R1Boc

HN Cl

ODCM/ RT/ 6hDCM ACN/ Reflux/ 4h

PTS-Cl/ TEA N N

OR1

NHBocCl

R1= CH3, Ph, Leu & Val

N N

OR1

NHBocI

R2

H2N OO

N NOR1

NHR2HN

OOO

O TFA/DCM

N NOR1

NH2. TFAR2HN

OOTEA /ACN

KI/Acetone

Finkelstein reaction A B

R2= Leu, Cys, Trp, Typ & His


Future Chemistry Scheme Execution

N N

ONH

R1 R2HNO

O

NNO HN

R1

R2 NH

O

BocDimarization

A X B

N N

ONH HN

O

NN

OHNNH

O

R1

R1

1) TFA/DCM

2) Coupling

N N

ONH

R1 R2HN

O

NNO NH

R1

R2 NH

O

NN

OHN

R1R2

NHO

O

N N

ONH

R1

R2HN

OBoc

NN

O

HNR1

R2

HN

O

NNO

NHR1

R2 HN

O NN

O

NHR1

R2

NH

O

N NO

HN

R1

R2NH

O

HH

HH

HH

H H

Coupling

1) TFA/DCM

2) Coupling

1) TFA/DCM2) Coupling


Application of SA peptidesApplication of SA peptides

New Materials Sensors Molecular electronics Ions Channels Antimicrobial


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