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. 2009 May 22;72(5):876-83.
doi: 10.1021/np800635h.

Antineoplastic agents. 565. Synthesis of combretastatin D-2 phosphate and dihydro-combretastatin D-2

Affiliations

Antineoplastic agents. 565. Synthesis of combretastatin D-2 phosphate and dihydro-combretastatin D-2

George R Pettit et al. J Nat Prod. .

Abstract

A modified synthetic route to combretastatin D-2 (5) was devised in order to further evaluate its biological activity, for its conversion to phosphate prodrugs (25-28), and as a route to obtaining dihydro-combretastatin D-2 (42). A parallel first total synthesis of dihydro-combretastatin D-2 was completed, proceeding from a saturated 3-phenylpropionic ester intermediate via the Ullmann biaryl ether reaction (39-41). In contrast to the cancer cell growth inhibitory activity exhibited by combretastatin D-2, relatively minor structural modifications (41, 42) caused elimination of those properties.

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Figures

Figure 1
Figure 1
Retrosynthesis of combretastatin D-2.
Figure 2
Figure 2
X-ray crystal structure of combretastatin D-2 (5) with 50% thermal ellipsoids.
Scheme 1
Scheme 1
Synthesis of 3-Phenylpropionic Acid Derivatives
Scheme 2
Scheme 2
Synthesis of Allylic Alcohol 19
Scheme 3
Scheme 3
Synthesis of Combretastatin D-2 (5) and Prodrug Salts
Scheme 4
Scheme 4
Attempted Synthesis of Nitro-combretastatin D-2 Benzyl and Methyl Ethers
Scheme 5
Scheme 5
Synthetic Routes to 3-Phenylpropyl Alcohol 38
Scheme 6
Scheme 6
Synthesis of Dihydro-combretastatin D-2 (42)

References

    1. For the preceding contribution (AA 564) refer to: Monk KA, Siles R, Hadimani MB, Mugabe BE, Ackley JF, Studerus SW, Edvardsen K, Trawick ML, Garner CM, Rhodes MR, Pettit GR, Pinney KG. Bioorg Med Chem. 2006;14:3231–3244.

    1. Pinney KG, Jelinek C, Edvardsen K, Chaplin DJ, Pettit GR. In: Anticancer Agents from Natural Products. Cragg GM, Kingston DGI, Newman DJ, editors. Chapter 3. CRC Press; Boca Raton, FL: 2005. pp. 23–46.
    1. Pettit GR, Cragg GM, Herald DL, Schmidt JM, Lohavani-jaya P. Can J Chem. 1982;60:1374–1376.
    1. Pettit GR, Singh SB, Cragg GM. J Org Chem. 1985;50:3404–3406.
    1. Pettit GR, Singh SB, Niven ML, Hamel E, Schmidt JM. J Nat Prod. 1987;50:119–131. - PubMed

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