Loblolly pine abietadienol/abietadienal oxidase PtAO (CYP720B1) is a multifunctional, multisubstrate cytochrome P450 monooxygenase.

Cytochrome P450 monooxygenases (P450s) are important enzymes for generating some of the enormous structural diversity of plant terpenoid secondary metabolites. In conifers, P450s are involved in the formation of a suite of diterpene resin acids (DRAs). Despite their important role in constitutive and induced oleoresin defense, a P450 gene of DRA formation has not yet been identified.

Inhibition of Chk1 by the G2 DNA damage checkpoint inhibitor isogranulatimide.

Inhibitors of the G(2) DNA damage checkpoint can selectively sensitize cancer cells with mutated p53 to killing by DNA-damaging agents. Isogranulatimide is a G(2) checkpoint inhibitor containing a unique indole/maleimide/imidazole skeleton identified in a phenotypic cell-based screen; however, the mechanism of action of isogranulatimide is unknown. Using natural and synthetic isogranulatimide analogues, we show that the imide nitrogen and a basic nitrogen at position 14 or 15 in the imidazole ring are important for checkpoint inhibition.

Total synthesis of (+/-)-13-methoxy-15-oxozoapatlin, a rearranged kaurane diterpenoid.

A 21-step linear synthesis of the structurally novel and biologically intriguing diterpenoid (+/-)-13-methoxy-15-oxozoapatlin (6) is described. Of particular note in this work is the development of a new method for the construction of the functionalized bicyclo[3.2.

Synthesis and antimitotic/cytotoxic activity of hemiasterlin analogues.

The antimitotic sponge tripeptide hemiasterlin (1) and a number of structural analogues have been synthesized and evaluated in cell-based assays for both cytotoxic and antimitotic activity in order to explore the SAR for this promising anticancer drug lead. One synthetic analogue, SPA110 (8), showed more potent in vitro cytotoxicty and antimitotic activity than the natural product hemiasterlin (1), and consequently it has been subjected to thorough preclinical evaluation and targeted for clinical evaluation. The details of the synthesis of hemiasterlin (1) and the analogues and a discussion of how their biological activities vary with their structures are presented in this paper.

Intramolecular conjugate addition of alkenyl and aryl functions to enones initiated by lithium-iodine exchange.

[reaction: see text]. Treatment of each of the substrates 20-26, 29, and 46-48 with t-BuLi in THF, in the presence of HMPA and TMSCl, provides good-to-excellent yields of the intramolecular conjugate addition products 30-36, 37, and 49-51, respectively.

A formal total synthesis of the sesterterpenoid (+/-)-dysidiolide and approaches to the syntheses of (+/-)-6-epi-, (+/-)-15-epi-, and (+/-)-6,15-bisepidysidiolide.

A formal total synthesis of the sesterterpenoid (+/-)-dysidiolide (1), a structurally novel sponge metabolite that inhibits the cdc25A protein phosphatase, and approaches to the syntheses of (+/-)-15-epi- (34), (+/-)-6-epi- (36), and (+/-)-6, 15-bisepidysidiolide (39) are described.

Total synthesis of the cyathane diterpenoid (+/-)-sarcodonin G.

[process--see text] The total synthesis of (+/-)-sarcodonin G (3), a highly functionalized member of the cyathane family of diterpenoids, is described.

CuCl-mediated intramolecular oxidative coupling of aryl- and alkenyltrimethylstannane functions.

[reaction: see text] The syntheses of bis-trimethylstannanes 8, 10, 12-14, 16, 18, 21, and 22 are described. Treatment of these substances with approximately 5 equiv of CuCl in DMF at rt for 30-60 min effects, in each case, oxidative coupling between the two sp2 carbon centers bearing the Me3Sn function to produce good-to-excellent yields of tricyclic products 23-31, respectively.

Improved synthesis of isogranulatimide, a G2 checkpoint inhibitor. Syntheses Of didemnimide C, isodidemnimide A, neodidemnimide A, 17-methylgranulatimide, and isogranulatimides A-C.

A concise, improved synthesis of isogranulatimide (6), a naturally occurring substance with G2 checkpoint inhibition activity, is described. Also reported are the syntheses of didemnimide C (18), isodidemnimide A (24), neodidemnimide A (36), 17-methylgranulatimide (9), and isogranulatimides A (10), B (11), and C (12). Compounds 9-12, congeners of isogranulatimide (6), are now available for biological evaluation.

High-throughput assay for G2 checkpoint inhibitors and identification of the structurally novel compound isogranulatimide.

Treatment of cancer cells lacking p53 function with G2 checkpoint inhibitors sensitizes them to the toxic effects of DNA damage and has been proposed as a strategy for cancer therapy. However, few inhibitors are known, and they have been found serendipitously. We report the development of a G2 checkpoint inhibition assay that is suitable for high-throughput screening and its application to a screen of 1300 natural extracts.