110720-12-2

Basic information

• Product Name: N-Z-didemnin A
• Synonyms: N-Z-didemnin A
• CAS NO: 110720-12-2
• Molecular Weight: 1077.33
• Mol File: 110720-12-2.mol

Chemical Properties

• CAS DataBase Reference: N-Z-didemnin A(CAS DataBase Reference)
• NIST Chemistry Reference: N-Z-didemnin A(110720-12-2)
• EPA Substance Registry System: N-Z-didemnin A(110720-12-2)

Safety Data

• Hazardous Substances Data: 110720-12-2(Hazardous Substances Data)

Upstream product

• 120286-04-6 (5S,8S,10S,14S,15R,18S,19R,22S,24aS)-18-Amino-15-((S)-sec-butyl)-14-hydroxy-5-isobutyl-10-isopropyl-22-(4-methoxy-benzyl)-8,19,23-trimethyl-tetradecahydro-11,20-dioxa-3a,6,16,23-tetraaza-cyclopentacyclotricosene-4,7,9,12,17,21,24-heptaone 
• 130008-93-4 cyclo--5-methylheptanoyl>oxy-3-oxo-2,5-dimethylhexanoyl>-L-leucyl>-L-prolyl-N,O-dimethyl-L-tyrosyl>-L-threonyl> hydrochloride 
• 120286-06-8 Z-(R)-MeLeu-SPY 
• 110720-18-8 H-Me₂Tyr-ONb 
• 110720-41-7 Z-D-MeLeu-Thr(OH)-O-Me₂Tyr-Pro-Leu-Hip-Ist-Boc 
• 110720-33-7 Z-D-MeLeu-Thr(OTMSe)-O-Me₂Tyr-Pro-Boc 
• 110720-34-8 Z-D-MeLeu-Thr(OTMSe)-O-Me₂Tyr-Pro-H 
• 110720-38-2 Boc-Ist(TBDMS)-Hip-Leu-OTMSe 
• 110720-31-5 Boc-Pro-Me₂Tyr-ONb 
• 110720-39-3 Boc-Ist-Hip-Leu-OH 
• 110720-26-8 Z-D-MeLeu-Thr-OTMSe 
• 110720-27-9 Bzl-Hip-Leu-OTMSe 
• 110720-32-6 Boc-Pro-Me₂Tyr-OH 
• 110720-28-0 H-Hip-Leu-OTMSe 

Downstream Products

• 77327-04-9 Didemnin A 
• 77327-06-1 didemnin C 
• 110720-13-3 O-(Lac)-benzyldidemnin C 
• 77327-05-0 didemnin B 
• 110720-14-4 O-(Lac)-benzyldidemnin B 
• 77327-04-9 didemnin A 
• 114607-50-0 didemnin B 
• 77327-06-1 didemnin C 
• 77327-05-0 didemnin B 
• 120286-10-4 N-(Z-L-Pro)didemnin A 
• 120286-05-7 Cyclo<(N-L-prolyl-N-methyl-D-leucyl)-O-<oxy>-3-oxo-2,5-dimethylhexanoyl>-L-leucyl>-L-prolyl-N,O-dimethyl-L-tyrosyl>-L-threonyl> 
• 77327-06-1 didemnin C 
• 120286-09-1 Z-didemnin C 
• 120286-08-0 Z-didemnin B 

Relevant articles and documents

Structure-activity relationships of the didemnins

Bioactivities of 42 didemnin congeners, either isolated from the marine tunicates Trididemnun solidum and Aplidium albicans or prepared synthetically and semisynthetically, have been compared. The growth inhibition of various murine and human tumor cells and plaque reduction of HSV-1 and VSV grown on cultured mammalian cells were used to assess cytotoxicity and antiviral activity. Biochemical assays for macromolecular synthesis (protein, DNA, and RNA) and enzyme inhibition (dihydrofolate reductase, thymidylate synthase, DNA polymerase, RNA polymerase, and topoisomerases I and II) were also performed to specify the mechanisms of action of each analogue. Immunosuppressive activity of the didemnins was determined using a mixed lymphocyte reaction (MLR) assay. These assays revealed that the native cyclic depsipeptide core is an essential structural requirement for most of the bioactivites of the didemnins, especially for cytotoxicities and antiviral activities. The linear side-chain portion of the peptide can be altered with a gain, in some cases, of bioactivities. In particular, dehydrodidemnin B, tested against several types of tumor cells and in in vivo studies in mice, as well as didemnin M, tested for the mixed lymphocyte reaction and graft vs host reaction in murine systems, showed remarkable gains in their in vitro and in vivo activities compared to didemnin B.

Synthesis of new didemnin B analogs for investigations of structure/biological activity relationships

Modifications were introduced in the side chain of didemnin B to afford several analogs (1f-1j) for biological testing in order to identify the features responsible for the bioactivity of the natural products (1a-1c). To achieve our goal, two changes were made in the proline ring of the b-turn side chain. Initially, a hydroxyl group was incorporated at the C-4 position of the ring to increase the polar nature of the molecule. Secondly, unsaturation was introduced at C-3 and C-4 to increase the rigidity of the ring and to provide a site for tritiation to follow the drug pathway in biological systems. Improvements were also introduced in the macrocycle construction to produce gram quantities of this unit (1d) for the preparation of the planned analogs. The linear precursor to the macrocycle was oxidized more effectively with 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (Dess-Martin periodinane reagent), and cyclization yields were increased substantially by using a new coupling reagent, pentafluorophenyl diphenylphosphinate (FDPP). (1H-1,2,3-benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP) and pentafluorophenyl trifluoroacetate were also used to improve other coupling reactions.

Total synthesis of the didemnins; IV. Synthesis of the peptolide ring and construction of the side chain

A total synthesis of didemnins A, B, and C (1-3) which enables these highly cytotoxic cyclopeptides to be prepared in decigram amounts is described. The β-keto acid unit (hydroxyisovaleryl)propionic acid derivative (Hip, 6) was prepared by acylation of dibenzyl methylmalonate and subsequent cleavage of the benzyl groups by the action of boron trichloride. The free β-keto acid 6 was activated by the DCC method and allowed to react with the leucine ester 7 to furnish the amide 8. Activation, deprotection, and ring closure of the linear peptide 19 by means of the pentafluorophenyl ester method in a two-phase system gave rise to the didemnin ring skeleton in 75% yield within a few minutes. The respective side chains were then attached to the didemnin ring easily and in high yields by activation of Z-(R)-N-methylleucine as its 3-cyano-2-pyridylthiol ester followed by reaction with Z-lactylproline chloride and Z-lactic acid chloride.