Post by: nick123 on February 06, 2013, 07:16:37 PM
I have a project in 5 days about α peptide which comes from snail conus magus called ziconotide... Does anybody know its synthesis??? I 've searched a lot of papers and internet sites of course and i didn't find anything...
Any help is appreciated!!
Post by: Arkcon on February 06, 2013, 10:01:02 PM
Post by: discodermolide on February 06, 2013, 11:53:27 PM
Post by: nick123 on February 07, 2013, 12:16:27 PM
Secondly i didnt find anything special except this... Its solid phase peptide synthesis method...
http://www.sciencedirect.com/science/article/pii/S0960894X9900699X take a look in the last picture Scheme 1...
Is it the synthesis for ziconotide???
Post by: Arkcon on February 07, 2013, 12:26:55 PM
Post by: nick123 on February 07, 2013, 12:39:44 PM
Conotoxin are polypeptides of 10-30 aminoacids with 1-3 disulfide bridges....
It comes from an sea marine poisonus snail called conus magus.
It is also a drug called prialt from ELan company...
Post by: discodermolide on February 07, 2013, 12:42:19 PM
It tells you how they cyclised the analogues.
Post by: nick123 on February 07, 2013, 12:53:07 PM
Have a look in J. Med. Chem. 2011, doi.org/10.1021/jm201060r, Crail G. J. etalEffects of Cyclization on Stability, Structure, and Activity of α-Conotoxin RgIA at the α9α10 Nicotinic Acetylcholine Receptor and GABAB Receptor.
It tells you how they cyclised the analogues.
Thanks but i cannot open the paper... it says that i have to pay in order to read it...
Post by: Arkcon on February 07, 2013, 01:16:57 PM
Its a polybasic peptide with 25 aminoacids connected with 3 disulfide bridges.
What odes that really mean?
Post by: nick123 on February 07, 2013, 01:26:29 PM
Post by: Arkcon on February 07, 2013, 01:39:56 PM
Post by: nick123 on February 07, 2013, 06:20:35 PM
I didnt find anything yet :-\
Post by: Arkcon on February 07, 2013, 08:58:36 PM
Quote
How was it discovered? How did it get to where it was discovered -- if that makes any sense?
Post by: discodermolide on February 09, 2013, 09:04:09 AM
C(NCC(N[C@@H](CCCCN)C(NCC(N[C@H](C(N[C@@H](CCCCN)C(N[C@H](C(N[C@@H](CO)C(N[C@@H](CCCNC(N)=N)C(N[C@@H](CC(C)C)C(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H](C(N[C@@H]([C@H](O)C)C(NCC(N[C@@H](CO)C(N[C@H](C(N[C@@H](CCCNC(N)=N)C(N[C@@H](CO)C(NCC(N[C@@H](CCCCN)C(N[C@H](C(N)=O)CS)=O)=O)=O)=O)=O)CS)=O)=O)=O)=O)CS)=O)CS)=O)CC(O)=O)=O)CC1=CC=C(O)C=C1)=O)CCSC)=O)=O)=O)=O)CS)=O)=O)C)=O)=O)=O)=O)=O)CS](https://www.chemicalforums.com/SMILES/400016d837a8cf7ee497.png)
Post by: nick123 on February 10, 2013, 02:25:27 PM
Where i can find full this paper??
Also i found this one
(https://www.chemicalforums.com/proxy.php?request=http%3A%2F%2Fars.els-cdn.com%2Fcontent%2Fimage%2F1-s2.0-S0009279712001962-gr3.jpg&hash=a214fcea804355c88c6b012d832a165ecbc1304e)
Fig. 3. Production of a cyclic bioengineered conopeptide: The peptide toxin parent sequence is initially bioengineered to introduce a N- to C-termini spacer/linker, together with OPG insertion to enable later selective disulfide bond formation. To enable N- to C-cyclization the thioester function group is strategically placed – this may require rearrangement of the linear construct to maximize ligation kinetics. In this example the –C–C– is used as the ligation position, this complies with chemical and kinetic requirements of Native Chemical Ligation. N- to C-termini peptide cyclisation is achieved via intramolecular attack of the C-terminal thioester by the N-terminal cysteine thiol. The resulting intermediate strucutre then undergoes spontaneous ring contraction through S,N acyl migration to form the cyclic peptide backbone – importantly resulting in a native-like peptide bond and the regeneration of the Cys thiol function. The now cyclic peptide is then selectively oxidized, the first control disulfide bond is formed between those existing free thiols, and then a secondary bond occurs with selective OPG deprotection and oxidation.
Is that image what i want???
Post by: discodermolide on February 10, 2013, 02:33:31 PM
The reference you will have to get from a university library.
Post by: nick123 on February 10, 2013, 02:39:05 PM
Post by: discodermolide on February 10, 2013, 02:47:30 PM
Post by: Arkcon on February 10, 2013, 02:48:33 PM
In either case, a peptide isn't made by adding functional groups to a carbon chain, as we generally do in organic chemistry, but instead one amino acid subunit is built upon another, one at a time.
There is also something functionally similar, but not a peptide, and you have a reference to that as well.
Post by: discodermolide on February 10, 2013, 02:52:06 PM
Post by: nick123 on February 10, 2013, 03:00:43 PM
I need an easy way which i can understand either my lecturers, in whom i m gonna make the presantation...
I am really very unhappy for the synthesis of this peptide... I search so many days and i didnt find something special...
I need a picture or a scheme...
I dont know the essential footsteps to make a peptide by myself.. I dont know many things for peptides either...
Thats why i ask for your help... Ιts not that i am boring or i want to spoil your time....
Post by: Arkcon on February 10, 2013, 04:00:27 PM
Post by: Arkcon on February 10, 2013, 04:06:01 PM
I got the Smiles for this compound, non-cyclised. It's enormous, and it's not quite how I would draw the chirality, here it is, feel free to delete it if it is too large.
Here's an question for you, discodermolide:. I doubt a sane person would prepare an peptide using organic synthesis instead of via biotechnology. But suppose, for academic reasons, they just felt like it. Could they? Could you build a chain of an amine and a carbons and a carbonyl and an amide and a carbon and a carbonyl and a ..., with or without the appropriate side groups?
Post by: nick123 on February 10, 2013, 05:07:56 PM
Is has a scheme for what i want... take a look
(https://www.chemicalforums.com/proxy.php?request=http%3A%2F%2Foi47.tinypic.com%2Fefl5zl.jpg&hash=d744020971d086fe403982f15d9cca7d0ebf60f9)
Now how can i explain that?? Could anybody tell me a general route for this synthesis??
Post by: discodermolide on February 10, 2013, 06:24:35 PM
I got the Smiles for this compound, non-cyclised. It's enormous, and it's not quite how I would draw the chirality, here it is, feel free to delete it if it is too large.
Here's an question for you, discodermolide:. I doubt a sane person would prepare an peptide using organic synthesis instead of via biotechnology. But suppose, for academic reasons, they just felt like it. Could they? Could you build a chain of an amine and a carbons and a carbonyl and an amide and a carbon and a carbonyl and a ..., with or without the appropriate side groups?
Some people do make peptides that way, usually on a resin and I believe that some very complex ones have been made. One company I know of had a decapeptide in production using resins. The problem with biotechnology is the extraction and purification process, but it is the way to go, no doubt.
Post by: discodermolide on February 10, 2013, 06:36:24 PM
The one on the left is a general one explaining how the achieved an acyl transfer reaction from one amino acid to another. This has been used in the conotoxin synthesis.
The second is the actual synthesis scheme. They start off with a 15 amino-acid fragment protected with 11 protecting groups, then make the tiobenzyl ester.
The next step is removal of all the protection and the acyl transfer and finally cleavage from the resin and cyclisation.
Do you know what the letters stand for, i.e. the sequence CKGKGA……..?
I mean I can draw it for you if you want, but it will take me a while to get it correct.
Post by: nick123 on February 10, 2013, 07:10:58 PM
So...
In the first step we have the first 15 amino acide sequence with the protecting groups, for example BOC for Lys, Trt for Cys and others... Fmoc is the protecting group for the N terminal of this sequence.
Then we protect the C terminal of the same sequence with Bzl/DIPCDI and with TFA/Phenol/EDT we remove all the protected groups (except Fmoc group).
In the next step we conjugate the second sequence (10 amino acids) and with perpidine we remove the fmoc group..
And finaly with oxidation we have the disulfide bridges of the peptide...
Is that right????
But i have some questions here...
1) TFA is the removing group for BOC and Trt i think. Whats the meaning of the Phenol/EDT/thioanisol????
2)The second sequense doesnt need protection groups to his amino acids? Or we conjugate it as is??? Ι try to say... why the first sequence must be protected and the second one no???
3)How do we unprotect the S-Bzl from the C terminal of the first sequence???
Post by: discodermolide on February 10, 2013, 07:36:06 PM
Then all the protecting groups are removed except for the Fmoc.
The next step is to carry out the S to N acyl transfer as per the other scheme with the two fragments.
Then piperidine removes the Fmoc and oxidation forms the disulphide bridges.
Questions:
1)The phenol/EDT/Thioanisol are there as radical trappers.
2)try and relate that on the right with that on the left. They carry out a S-N acyl transfer so you have a Sbenzyl ester on onside, along comes a second peptide with a cya on the end, you get an ester exchange and an acyl migration according to the left hand diagram.
3)Answered in 2 above.
Post by: nick123 on February 10, 2013, 07:55:53 PM
But my question remains!!!
Why then do we have to protect the first sequence??? let me try to answer...
Because we need the conjugate ONLY on the C terminal of the first sequence otherwise without protection groups the nucleophilic substitution will happen from S to many carbons of the first sequence...
Right???
Post by: discodermolide on February 10, 2013, 08:00:19 PM
here is my reaction scheme without all the protection. I hope it makes sense.
Post by: discodermolide on February 10, 2013, 08:06:28 PM
Post by: discodermolide on February 10, 2013, 08:08:19 PM
![[H]N[C@@H](CSSC[C@@H](C(N[C@@H]([C@H](O)C)C(NCC1=O)=O)=O)NC2=O)C(N[C@@H](CCCCN)C(NCC(N[C@@H](CCCCN)C(NCC(N[C@H](C(N[C@@H](CCCCN)C(N[C@@H](CSSC[C@@H](C(N[C@@H](CCCNC(N)=N)C(N[C@@H](CO)C(NCC3=O)=O)=O)=O)NC([C@H](CO)N1)=O)C(N[C@@H](CO)C(N[C@@H](CCCNC(N)=N)C(N[C@@H](CC(C)C)C(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H]2CSSC[C@@H](C(O)=O)NC([C@H](CCCCN)N3)=O)=O)CC(O)=O)=O)CC4=CC=C(O)C=C4)=O)CCSC)=O)=O)=O)=O)=O)=O)C)=O)=O)=O)=O)=O](https://www.chemicalforums.com/SMILES/bdabfb6715d695194b9d.png)
Post by: nick123 on February 10, 2013, 08:18:52 PM
Thank you with all my heart!!!
And the member Arkcon of course but your help was crucial!
Post by: Babcock_Hall on February 11, 2013, 09:59:59 AM
Post by: nick123 on February 23, 2013, 02:06:09 AM
Post by: nick123 on February 23, 2013, 01:13:50 PM
Post by: discodermolide on February 23, 2013, 02:09:56 PM
Post by: nick123 on February 23, 2013, 05:39:09 PM
Post by: sjb on February 23, 2013, 07:33:44 PM
This one does not have an IUPAC name.
Eh? Of course it does, admittedly it'll be very complex here, but why do you feel it has no name?
Post by: discodermolide on February 23, 2013, 09:16:36 PM
I would not care to work out the longest chain here.