The bryostatins are macrocyclic lactones that represent an additional structural class of potent activators of protein kinase C. These marine animal biosynthetic products are of unusual interest because they induce only a subset of the biological responses induced by the phorbol esters. We have now determined the binding affinities of naturally occurring and semisynthetic bryostatins for protein kinase C by competition analysis with [26-3Hlbryostatin 4 as the radioactive ligand. Esterification of the hydroxyl group at C26 caused dramatic loss of activity as did inversion of the asymmetric center at this position. In contrast, neither of the ester groups at C7 and C20 had a major influence on activity. Computer modeling of the phorbol esters, related diterpenes, and indole alkaloids suggested that the C20, C9, and C4 oxygens of phorbol represented critical elements of the phorbol ester pharmacophore. The C26 oxygen of the bryostatins, together with the C1 and C19 oxygens, gave an excellent spatial correlation with this model, with a root-mean-square deviation of 0.16 A (compared to 0.10-0.35 A among phorbol-related diterpenes). The extension of the phorbol ester pharmacophore model to the bryostatins and its agreement with the structureactivity relations for the bryostatin class of compounds provide additional support for the validity of the model. Protein kinase C mediates one arm of the signal-transduction pathway proceeding through inositol phospholipid breakdown (1,2). This pathway is directly involved in the action of a broad range of cellular effectors, including growth factors and oncogenes, and indirectly affects other transduction pathways such as that of the cyclic AMP second-messenger system. Protein kinase C is proposed to be activated by 1,2-diacyl-sn-glycerol compounds and by certain exogenous analogs such as the phorbol ester tumor promoters (3, 4). In addition to the phorbol esters and related diterpenes, a number of structurally distinct natural products have been identified that also bind to protein kinase C with high affinity and that resemble the phorbol esters in their actions at nanomolar concentrations in biological systems. These compounds include the indole alkaloids such as teleocidin and the polyacetates such as aplysiatoxin (5).Recently, considerable attention has focused on an unusual class of potent activators of protein kinase C, the bryostatins. These compounds are macrocyclic lactones isolated from Bugula neritina and other marine bryozoans on the basis of antineoplastic activity against the P388 leukemia cell system (6). The bryostatins at nanomolar concentrations inhibit phorbol ester binding to protein kinase C and stimulate enzymatic activity in vitro to a comparable degree as do the phorbol esters (7-9). Biologically, however, the bryostatins induce only a subset of the typical phorbol ester responses. Moreover, the bryostatins block, in an apparently noncompetitive fashion, the action of the phorbol esters on those responses that they themselves do not induce. Exampl...

6-Azaandrost-4-en-3-ones were synthesized and tested versus human type 1 and 2 steroid 5 alpha-reductase (5AR) and human adrenal 3 beta-hydroxy-delta 5-steroid dehydrogenase/3-keto-delta 5-steroid isomerase (3BHSD) to explore the structure-activity relationship of this novel series in order to optimize potency versus both isozymes of 5AR and selectivity versus 3BHSD. Compounds with picomolar IC50's versus human type 2 5AR and low nanomolar Ki's versus human type 1 5AR with 100-fold selectivity versus 3BHSD were identified (70). Preliminary in vivo evaluation of some optimal compounds from this series in a chronic castrated rat model of 5AR inhibitor-induced prostate involution and dog pharmacokinetic measurements identified a series of 17 beta-[N-(diphenylmethyl)carbamoyl]-6-azaandrost-4-en-3-ones (compounds 54, 66, and 67) with good in vivo efficacy and half-life in the dog. Inhibitors with, at the minimum, low nanomolar potency toward both human 5AR's and selectivity versus 3BHSD may show advantages over previously known 5AR inhibitors in the treatment of disease states which depend upon dihydrotestosterone, such as benign prostatic hyperplasia.

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delta.5-steroid Dehydrogenase/3-Keto-δ5-steroid Isomerase. -Seventy-seven compounds of type (I) and (II) are tested to explore the structure-activity relationship in order to optimize potency versus both isozymes of 5α-reductase and selectivity versus the human adrenal 3BHSD. The derivative (Ib) (R3: -NH-CH(p-ClC6H4)2) is a potent dual inhibitor of type 1 and 2 human 5AR with selectivity versus 3BHSD in vivo. -(FRYE, S. V.; HAFFNER, C. D.; MALONEY, P. R.; MOOK, R. A. JUN.; DORSEY, G. F. JUN.; HINER, R. N.; CRIBBS, C. M.; WHEELER, T. N.; RAY, J. A.; ANDREWS, R. C.; BATCHELOR, K. W.; BRAMSON, H. N.; STUART, J. D.; SCHWEIKER, S. L.; VAN ARNOLD, J.; CROOM, S.; BICKETT, D. M.; MOSS, M. L.; TIAN, G.; UNWALLA, R.

TriphenylphosphinePh 3 P [603-35-0] C 18 H 15 P (MW 262.30) InChI = 1/C18H15P/c1-

No abstract

Dihydropyrano[2,3-b]pyridylimidazolinonesand related compounds represent a new series in the imidazolinone herbicide family developed by American Cyanamid Company. The synthesis of the parent compound was accomplished by a novel enaminone-directed cyclization to the pyrano ring in the key step.These compounds showed excellent herbicidal activity with soybean selectivity. The intensive chemical synthesis program on the pyridylimidazolinone herbicides at the Agricultural Research Division of American Cyanamid resulted in the discovery of several important crop protection products (1-7).Among them are 2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)nicotinic acid 1 (AC 243,997, imazapyr) and its isopropylamine salt 2 (AC 252,925) registered by American Cyanamid as ARSENAL, ASSAULT and CHOPPER total vegetation control herbicides.Attachment of a benzo ring to the pyridine ring in 1 forms a quinoline analog, 3 (AC 252,214, imazaquin, registered by American Cyanamid under the trademark SCEPTER). This compound exhibits excellent safety on soybeans while maintaining control of a wide range of weeds.

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