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DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER

Specific Stereoisomeric Conformations Determine the Drug Potency of Cladosporin Scaffold against Malarial Parasite

 Uncategorized  Comments Off on Specific Stereoisomeric Conformations Determine the Drug Potency of Cladosporin Scaffold against Malarial Parasite
May 272018
 

 

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Specific Stereoisomeric Conformations Determine the Drug Potency of Cladosporin Scaffold against Malarial Parasite

https://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.8b00565

Pronay Das†ab, Palak Babbar†c, Nipun Malhotra†c, Manmohan Sharmac , Goraknath R. Jachakab , Rajesh G. Gonnadebd, Dhanasekaran Shanmugambe, Karl Harlosf , Manickam Yogavelc , Amit Sharmac *, and D. Srinivasa Reddyab* †All three have contributed equally to this work.
aOrganic Chemistry Division, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411008, India
b Academy of Scientific and Innovative Research (AcSIR), New Delhi 110025, India
cMolecular Medicine Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), New Delhi 110067, India dCenter for Material Characterization, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411008, India
e Biochemical Sciences Division, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411008, India
fDivision of Structural Biology, Welcome Trust Centre for Human Genetics, The Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK
J. Med. Chem., Just Accepted Manuscript
DOI: 10.1021/acs.jmedchem.8b00565
Publication Date (Web): May 21, 2018
Copyright © 2018 American Chemical Society
The dependence of drug potency on diastereomeric configurations is a key facet. Using a novel general divergent synthetic route for a three-chiral centre anti-malarial natural product cladosporin, we built its complete library of stereoisomers (cladologs) and assessed their inhibitory potential using parasite-, enzyme- and structure-based assays.
We show that potency is manifest via tetrahyropyran ring conformations that are housed in the ribose binding pocket of parasite lysyl tRNA synthetase (KRS). Strikingly, drug potency between top and worst enantiomers varied 500-fold, and structures of KRS-cladolog complexes reveal that alterations at C3 and C10 are detrimental to drug potency where changes at C3 are sensed by rotameric flipping of Glutamate332.
Given that scores of anti-malarial and anti-infective drugs contain chiral centers, this work provides a new foundation for focusing on inhibitor stereochemistry as a facet of anti-microbial drug development.
Cladosporin (12) displays exquisite selectivity for the parasite lysyl-tRNA synthetase over human enzyme. This species specific selectivity of cladosporin has been previously described through comprehensive sequence alignment, where the residues val329 and ser346 seem to be sterically crucial for accommodating the methyl moiety of THP ring10. The structural features of compound 12 clearly indicate the presence of three stereocenters, and therefore 2n (n=3) i.e., eight stereoisomers are possible (Fig.1). Till date, only one asymmetric total synthesis of cladosporin13 has been achieved which was followed by another report of formal syntheses14. Here, we have developed a general chemical synthesis route to synthetically access all the eight possible stereoisomers of compound 12.
cladosporin (compound 12) (0.052 g) as a white solid with a yield of 54 %. Melting point: 171-173 °C; [α]25 D = -15.75 (c = 0.6, EtOH); IR υmax(film): cm-1 3416, 3022, 1656, 1218; 1H NMR (400 MHz, CDCl3): δ 11.06 (s, 1H), 7.47 (br. s., 1H), 6.29 (s, 1H), 6.16 (s, 1H), 4.68 (t, J = 9.8 Hz, 1H), 4.12 (s, 1H), 4.01 (s, 1H), 2.89 – 2.75 (m, 2H), 2.00 – 1.94 (m, 1H), 1.87 – 1.81 (m, 1H), 1.70 – 1.63 (m, 4H), 1.35 (d, J = 6.1 Hz, 2H), 1.23 (d, J = 6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 169.9, 164.3, 163.1, 141.8, 106.7, 102.0, 101.5, 76.3, 68.0, 66.6, 39.3, 33.6, 30.9, 18.9, 18.1; HRMS calculated for C16H21O5 [M + H]+ 293.1384, observed 293.1379.
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Dr. D. Srinivasa Reddy has been appointed as an editor of Bioorganic & Medicinl Chemistry Letters, Elsevier Publications. Congratulation Sir !

Click here for details. https://www.journals.elsevier.com/bioorganic-and-medicinal-chemistry-letters

The research interests of his group lie in issues related to application of oriented organic synthesis, in particular total synthesis of biologically active natural products, medicinal chemistry and crop protection. This team has been credited with having accomplished total synthesis of more than 25 natural products with impressive biological activities. “Some of our recent achievements include identification of potential leads, like antibiotic compound based on hunanamycin natural product for treating food infections, anti-diabetic molecule in collaboration with an industry partner and  anti-TB compound using a strategy called ‘re-purposing of a drug scaffold’,” said Reddy.

A total of two awardees out of four were from CSIR institutes. In addition to Reddy, Rajan Shankarnarayanan, CSIR – CCMB, Hyderabad (basic sciences), also was conferred with the award. Vikram Mathews, CMC, Vellore (medical research) and Prof Ashish Suri, AIIMS, New Delhi (clinical research), were the others to receive the awards.

With more than 80 scientific publications and 35 patents, Reddy is one of the most prominent scientists in the city and has already been honoured with the Shanti Swarup Bhatnagar prize in chemical sciences. Reddy is also a nominated member of the scientific body of Indian Pharmacopoeia, government of India and was  elected as a fellow of the Telangana and Maharashtra Academies of Sciences in addition to the National Academy of Sciences, India (NASI).

//////////CLADOSPORIN, NCL, CSIR, SRINIVASA REDDY, PUNE, MALARIA
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Continuous Flow Doebner–Miller Reaction and Isolation Using Continuous Stirred Tank Reactors

 PROCESS, Uncategorized  Comments Off on Continuous Flow Doebner–Miller Reaction and Isolation Using Continuous Stirred Tank Reactors
Aug 312016
 

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Continuous flow Doebner–Miller synthesis of different quinaldines from respective anilines is demonstrated using sulfuric acid as a homogeneous catalyst. The extent of reaction was monitored for various parameters, namely, temperature, residence time, mole ratio of sulfuric acid to substrate, mole ratio of crotonaldehyde to substrate, and so forth. Continuous stirred reactors in series were used as a preferred configuration for this rection that generates byproduct in the form of sticky solid material. The approach has been extended for six different anilines, and the results are compared with batch reactions. Continuous stirred reactors in series with distributed dosing of crotonaldehyde facilitated a continuous flow reaction with lower byproduct formation, increased yields, and continuous workup and is a scalable approach.

 

Continuous Flow Doebner–Miller Reaction and Isolation Using Continuous Stirred Tank Reactors

Chem. Eng. & Process Dev. Division, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pashan, Pune 411 008, India
Organic Chemistry Division, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pashan, Pune 411 008, India
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.6b00179
Publication Date (Web): August 22, 2016
Copyright © 2016 American Chemical Society
*E-mail: aa.kulkarni@ncl.res.in. Fax: +91-20-25902621.
Image result for Maruti B. Yadav ncl
Mr. Maruti Yadav
Project Assistant
M.Sc. Organic Chemistry, Pune University, 2013
Process Development of API production in continuous flow
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Image result for amol kulkarni ncl
Dr. Amol A. Kulkarni

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Dr. Amol A. Kulkarni is a Scientist in the Chemical Engineering Division at the National Chemical Laboratory. He did his B. Chem. Eng. (1998), M. Chem. Eng (2000) and Ph.D. in chemical engineering (2003) all from the University Dept. of Chem. Technology (UDCT, Mumbai). In 2004 he worked at the Max Planck Institute-Magdeburg (Germany) as a Alexander von Humboldt Research Fellow. At NCL he is driving a research program on the design of microreactors and exploring their applications for continuous syntheses including of nanoparticles. He has been awarded with the Max-Planck-Visiting Fellowship from the Max-Planck-Society, Munich for 2008-2011. His research areas include: (i) design and applications of microreactors, (ii) design of multiphase reactors, (iii) experimental and computational fluid dynamics, and (iv) nonlinear dynamics of coupled systems. He is an active member of Initiative for Research and Innovation in Science (IRIS) supported by Intel’s Education Initiative to organize National Science Fair and popularize science in India.

Research areas

  • Multiphase reactors and Microreactors
  • Process Development and Scale-up
  • Process Intensification & MAGIC Processes
  • Industrial Flow Processes

Contact

  • Dr. Amol A. Kulkarni
    Scientist
    Office: 529, PP-1 Building, CEPD
    National Chemical Laboratory
    Dr. Homi Bhabha Road
    Pune 411008, India
    Phone  +91 20 2590 2153
    Fax +91 20 2590 2621
    E-mail aa.kulkarni@ncl.res.in

///////////Continuous Flow,  Doebner–Miller Reaction, Isolation, Continuous Stirred Tank Reactors, chemical engeineering, process, Amol A. Kulkarni, ncl, pune

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Flow Chemistry Symposium + Workshop on 27-28th Aug’ 2016 at IISER – PUNE, Pune, India

 SYNTHESIS  Comments Off on Flow Chemistry Symposium + Workshop on 27-28th Aug’ 2016 at IISER – PUNE, Pune, India
Aug 192016
 

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Flow Chemistry Society – India Chapter is assisting the proliferation of Process Intensification and Flow Chemistry across the country

After  an  enthusiastic  response  at the  2nd FCS-India Symposium & Workshop held at IICT-Hyderabad  in June’16  with  27companies and 115 delegates attending,  we are happy to announce :

The 3rd   2-day FLOW CHEMISTRY Symposium + DEMO Workshop is organized on 27th – 28th August 2016 at  IISER – PUNE  by Flow Chemistry Society – India Chapter (in collaboration with IISER-Pune,  NCL  & IIT-B) ,  with speakers & demonstrators from India, UK, Netherlands and Hungary.

Prof. Ashwini Kumar Nangia,  Director – CSIR-NCL has kindly consented to be the Hon. Chief Guest and inaugurate the Symposium & Workshop.

Both days have intensive interactive sessions on the theory and industrial applications of Flow Chemistry followed by  livedemonstrations  using              5 to 6 different Flow Reactor platforms –each day  from microliters to 10,000 L/day  industrial scale.

The Fees are Rs. 7,000 for Industry Delegates and Rs. 3,000 for Academic Delegates

The registration form  is BELOW

CLICK FOR REGISTRATION FORM 1-REGISTRATION FORM

contact : vk@pi-inc.co   or   msingh@cipla.com   or    rentala@inkarp.co.in 

Accomodation (optional)  : for Bookings please contact IISER-Pune Guest House directly

Mr. Charu Gurav; Mgr Guest Hse, managergh@iiserpune.ac.in   020-25908130    OR

Mr. Sreejit, Mgr-Catering, etc.    sreejit@iiserpune.ac.in    020-25908247

Tariff  per room night :  Rs. 1,500 (single occupancy) //  Rs. 2,000 (Double Occupancy)

best regards

 Vijay

                             Flow Chemistry Society – India Chapter

Vijay Kirpalani                                                                                      Manjinder Singh
President                                                                                Vice-President
email : vk@pi-inc.co                                                                         email : msingh@cipla.com

Tel: +91-9321342022                                                          Tel: +91-9321342022

CLICK FOR REGISTRATION FORM 1-REGISTRATION FORM

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Day 16 of the 2016 Doodle Fruit Games! Find out more at g.co/fruit

P V SINDHU OF INDIA WINS SILVER AT RIO 2016 OLYMPICS IN BADMINTON

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Welcome Scientific update to Pune, India 2-3 and 4-5 Dec 2014 for celebrating Process chemistry

 companies, PROCESS  Comments Off on Welcome Scientific update to Pune, India 2-3 and 4-5 Dec 2014 for celebrating Process chemistry
Sep 292014
 

 

WEBSITE http://www.scientificupdate.co.uk/

SCIENTIFIC UPDATE HAS A REPUTATION FOR ITS HIGH QUALITY EVENTS, BOTH FOR THE SCIENTIFIC CONTENT AND ALSO FOR THE EFFICIENCY OF ITS ORGANISATION. KEEP YOUR SKILLS UP TO DATE AND INVEST IN YOUR CONTINUING PERSONAL PROFESSIONAL DEVELOPMENT.

http://makeinindia.com/

TRAINING COURSE   2-3 DEC 2014

Process Development for Low Cost Manufacturing

When:02.12.2014 – 03.12.2014

Tutors:

Where: National Chemical Laboratory – Pune, India

Brochure:View Brochure

Register http://scientificupdate.co.uk/training/scheduled-training-courses.html

 

DESCRIPTION

Chemical process research and development is recognised as a key function during the commercialisation of a new product particularly in the generic and contract manufacturing arms of the chemical, agrochemical and pharmaceutical industries.

The synthesis and individual processes must be economic, safe and must generate product that meets the necessary quality requirements.

This 2-day course presented by highly experienced process chemists will concentrate on the development and optimisation of efficient processes to target molecules with an emphasis on raw material cost, solvent choice, yield improvement, process efficiency and work up, and waste minimisation.

Process robustness testing and reaction optimisation via stastical methods will also be covered.

A discussion of patent issues and areas where engineering and technology can help reduce operating costs.

The use of engineering and technology solutions to reduce costs will be discussed and throughout the course the emphasis will be on minimising costs and maximising returns.

 

 

Conference 4-5 DEC 2014

TITLE . Organic Process Research & Development – India

Subtitle:The 32nd International Conference and Exhibition

When:04.12.2014 – 05.12.2014

Where:National Chemical Laboratory – Pune, India

Brochure:View Brochure

Register..http://scientificupdate.co.uk/conferences/conferences-and-workshops.html

Organic Process Research & Development - India

for

  • Process Research & Development Chemists
  • Chemical Engineers in Industry
  • Heads of Departments & Team Leaders

Benefits

  • Invest in yourself: keeping up to date on current developments and future trends could mean greater job security.
  • Learn from a wide range of industrial case studies given by hand-picked industrial speakers.
  • Take home relevant ideas and information that are directly applicable to your own work with the full proceedings and a CD of the talks.
  • Save time. Our intensive, commercial-free programme means less time away from work.
  • Meet and network with the key people in the industry in a relaxed and informal atmosphere.

Do you want to improve efficiency and innovation in your synthetic route design, development and optimisation?

The efficient conversion of a chemical process into a process for manufacture on tonnage scale has always been of importance in the chemical and pharmaceutical industries. However, in the current economic and regulatory climate, it has become increasingly vital and challenging to do so efficiently. Indeed, it has never been so important to keep up to date with the latest developments in this dynamic field.

At this Organic Process Research & Development Conference, you will hear detailed presentations and case studies from top international chemists. The hand-picked programme of speakers has been put together specifically for an industrial audience. They will discuss the latest issues relating to synthetic route design, development and optimisation in the pharmaceutical, fine chemical and allied fields.  Unlike other conferences, practically all our speakers are experts from industry, which means the ideas and information you take home will be directly applicable to your own work.

The smaller numbers at our conferences create a more intimate atmosphere. You will enjoy plenty of opportunities to meet and network with speakers and fellow attendees during the reception, sit-down lunches and extended coffee breaks in a relaxed and informal environment. Together, you can explore the different strategies and tactics evolving to meet today’s challenges.

This is held in Pune, close proximity to Mumbai city, very convenient to stay and travel to either in Pune or Mumbai. I feel this should be an opportunity to be grabbed before the conference is full and having no room

Hurry up rush

References

http://newdrugapprovals.org/scientificupdate-uk-on-a-roll/

http://scientificupdate.co.uk/conferences/conferences-and-workshops.html

http://en.wikipedia.org/wiki/Pune

PROFILES

Will Watson

Will Watson

Dr Will Watson gained his PhD in Organic Chemistry from the University of Leeds in 1980. He joined the BP Research Centre at Sunbury-on-Thames and spent five and a half years working as a research chemist on a variety of topics including catalytic dewaxing, residue upgrading, synthesis of novel oxygenates for use as gasoline supplements, surfactants for use as gasoline detergent additives and non-linear optical compounds.

In 1986 he joined Lancaster Synthesis and during the next 7 years he was responsible for laboratory scale production and process research and development to support Lancaster’s catalogue, semi-bulk and custom synthesis businesses.

In 1993 he was appointed to the position of Technical Director, responsible for all Production (Laboratory and Pilot Plant scale), Process Research and Development, Engineering and Quality Control. He helped set up and run the Lancaster Laboratories near Chennai, India and had technical responsibility for the former PCR laboratories at Gainesville, Florida.

He joined Scientific Update as Technical Director in May 2000. He has revised and rewritten the ‘Chemical Development and Scale Up in the Fine Chemical & Pharmaceutical Industries’ course and gives this course regularly around the world. He has been instrumental in setting up and developing new courses such as ‘Interfacing Chemistry with Patents’ and ‘Making and Using Fluoroorganic Molecules’.

He is also involved in an advisory capacity in setting up conferences and in the running of the events. He is active in the consultancy side of the business and sits on the Scientific Advisory Boards of various companies.

………………………………………………………………………………………………….

John Knight

John Knight

Dr John Knight gained a first class honours degree in chemistry at the University of Southampton, UK. John remained at Southampton to study for his PhD in synthetic methodology utilizing radical cyclisation and dipolar cyloaddition chemistry.

After gaining his PhD, John moved to Columbia University, New York, USA where he worked as a NATO Postdoctoral Fellow with Professor Gilbert Stork. John returned to the UK in 1987 joining Glaxo Group Research (now GSK) as a medicinal chemist, where he remained for 4 years before moving to the process research and development department at Glaxo, where he remained for a further 3½ years.

During his time at Glaxo, John worked on a number of projects and gained considerable plant experience (pilot and manufacturing). In 1994 John moved to Oxford Asymmetry (later changing its name to Evotec and most recently to Aptuit) when it had just 25 staff. John’s major role when first at Oxford Asymmetry was to work with a consultant project manager to design, build and commission a small pilot plant, whilst in parallel developing the chemistry PRD effort at Oxford Asymmetry.

The plant was fully operational within 18 months, operating to a 24h/7d shift pattern. John continued to run the pilot plant for a further 3 years, during which time he had considerable input into the design of a second plant, which was completed and commissioned in 2000. After an 18-month period at a small pharmaceutical company, John returned to Oxford in 2000 (by now called Evotec) to head the PRD department. John remained in this position for 6.5 years, during which time he assisted in its expansion, established a team to perform polymorph and salt screening studies and established and maintained high standards of development expertise across the department.

John has managed the chemical development and transfer of numerous NCE’s into the plant for clients and been involved in process validations. He joined Scientific Update in January 2008 as Scientific Director.

Pune images

From top: Fergusson College, Mahatma Gandhi Road (left), Shaniwarwada (right), the HSBC Global Technology India Headquarters, and the National War Memorial Southern Command
From top:1 Fergusson College, 2 Mahatma Gandhi RoadShaniwarwada 3 the HSBC Global Technology India Headquarters, and the 4National War Memorial Southern Command

 

NCL PUNE

The National Chemical Laboratory is located in the state of Maharashtra in India. Maharashtra state is the largest contributor to India’s GDP. The National Chemical Laboratory is located in Pune city, and is the cultural capital of Maharashtra. Pune city is second only to Mumbai (the business capital of India) in size and industrial strength. Pune points of interest include: The tourist places in Pune include: Lal Deval Synagogue, Bund Garden, Osho Ashram, Shindyanchi Chhatri and Pataleshwar Cave Temple.

http://makeinindia.com/

MAKE IN INDIA

http://makeinindia.com/

http://makeinindia.com/sector/pharmaceuticals/

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

 

 

 

KEYWORDS

JOHN KNIGHT, WILL WATSON,  SCIENTIFIC UPDATE, PROCESS, COURSE, CONFERENCE, INDIA, PUNE, PROCESS DEVELOPMENT, LOW COST,  MANUFACTURING, SCALEUP

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