Structure of Dolastatin 10
Structure of Dolastatin 10

Dolastatin 10
Systematic name: N,N-Dimethyl-L-valyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-oxo-3-{[(1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethyl]amino}propyl]-1-pyrrolidinyl}-5-methyl-1-oxo-4-heptanyl]-N-methyl-L -valinamide
Molecular Formula: C42H68N6O6S
Molecular weight 785.09092 g/mol
Average mass: 785.091 Da
Monoisotopic mass: 784.492126 Da


Structure of Dolastatin 15
Structure of Dolastatin 15

Dolastatin 15
Systematic name
(2S)-1-[(2S)-2-Benzyl-3-methoxy-5-oxo-2,5-dihydro-1H-pyrrol-1-yl]-3-methyl-1-oxo-2-butanyl N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-L-prol
Molecular Formula: C45H68N6O9
Molecular weight: 837.05622 g/mol
Average mass: 837.056 Da
Monoisotopic mass: 836.504761 Da


Dolastatin 10 and dolastatin 15 are marine natural products isolated from the Indian Ocean sea hare Dollabella auriculariaThis potent antitumor agent is also isolated from the marine cyanobacterium Symploca sp. VP642 from Palau.  Being a small linear peptide molecules, dolastatin 10 and 15 are considered promising anti-cancer drugs showing potency against breast and liver cancers, solid tumors and some leukemias. Preclinical research indicated potency in experimental antineoplastic and tubulin assembly systems. The dolastatins are mitotic inhibitors. They inhibits microtubule assembly by interfering with tubulin formation and thereby disrupt cell division by mitosis and induces apoptosis and Bcl-2 phosphorylation in several malignant cell types.[1][2]

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These molecules noncompetitively inhibits binding of vincristine to tubulin (at a location known as the vinca/peptide region) but have been shown to bind to the RZX/MAY region.  [1][2]

Chemically related to Symplostatin
The dolastatins (dolastatin 10 and dolastatin 15) are chemically related to analogue symplostatin 1which has been re-isolated from Guamanian and Hawaiian varieties of S. hydnoides. Its total stereochemistry was completed by determining the N,N-dimethylisoleucine unit to be l. Symplostatin 1,which is, like dolastatin 10, is a potent microtubule inhibitor. In addition, the antitumor activity of Symplostatin 1 was assessed in vivo against several murine tumors. Symplostatin 1 was effective against a drug-insensitive mammary tumor and a drug-insensitive colon tumor.  The drug was, however, only slightly effective against two multi-drug resistant (MDR) tumors.[3]

Researchers have isolated symplostatin 3, ananalogue of dolastatin 10, from a tumor selective extract of the Hawaiian variety of the marine cyanobacterium Symploca spVP452. Symplostatin 3 differs from dolastatin 10 only in the C-terminal unit. The dolaphenine unit is substituted by a 3-phenyllactic acidresidue.  Symplostatin 3 possesses IC(50) values for in vitro cytotoxicity toward human tumor cell lines ranging from 3.9 to 10.3 nM. It disrupts microtubules, but at a higher concentration than dolastatin 10, correlating with the weaker in vitro cytotoxicity.[4]

Auristatins are potent synthetic analogs of dolastatin 10.


References

[1] Amador, M.L., Jimeno, J., Paz-Ares, L., Cortes-Funes, H., M. Hidalgo. Progress in the development and acquisition of anticancer agents from marine sources. Annals of Oncology (2003) 14:1607-1615.[2] Kijjoa A and P Sawangwong. Drugs and cosmetics from the sea (review paper). Mar. Drugs 2004:73-82.

[3] Luesch H, Moore RE, Paul VJ, Mooberry SL, Corbett TH. Isolation of dolastatin 10 from the marine cyanobacterium Symploca species VP642 and total stereochemistry and biological evaluation of its analogue symplostatin 1. J Nat Prod. 2001 Jul;64(7):907-10.

[4] Luesch H, Yoshida WY, Moore RE, Paul VJ, Mooberry SL, Corbett TH.Symplostatin 3, a new dolastatin 10 analogue from the marine cyanobacterium Symploca sp. VP452. J Nat Prod. 2002 Jan;65(1):16-20.

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