Synthesis and post-coital contraceptive activity of ether and ester analogues of 2,3-diaryl-2H-1-benzopyrans.

Ether and ester analogues of 2,3-diaryl-2H-1-benzopyrans have been synthesised and tested for their pregnancy inhibiting activity in immature rats. Some of the compounds exhibit potent activity. Structure-activity relationship relative to the hydroxy analogue has been discussed. In general, esters were found to be better inhibitory agents.

RH-5849, a nonsteroidal ecdysone agonist, does not mimic makisterone-A in Dysdercus koenigii.

The response of final instar nymphs of Dysdercus koenigii to topical application of the non-steroidal ecdysone agonist, RH-5849, was dose dependent. The candidate compound produced mortality even at moderate doses, but precocious adult development was not observed. Similar results were obtained after oral administration or injection. Conversely, injections of makisterone-A (the principal moulting hormone of Dysdercus) into 5th instar nymphs resulted in precocious adult development within 4 days. We conclude that RH-5849 does not mimic makisterone-A, as is the case with ecdysone, and that toxicity is mediated instead through non-endocrine targets in this insect species.

Structure of lansimide 2, a product from Clausena lansium.

The natural product lansimide 2 is a 1:1 mixture of two different cyclic amides, C18H17NO2.C18H19NO3. The mixture crystallizes as a molecular pair in the centrosymmetric space group P21/n. M(r) = 576.69, monoclinic, a = 20.151 (2), b = 6.2984 (4), c = 24.051 (2) A, beta = 104.339 (8) degrees, V = 2957.4 A3, Z = 4, Dx = 1.30 g cm-3, Cu K alpha, lambda = 1.54178 A, mu = 6.1 cm-1, F(000) = 1224, T = 163 (1) K, R = 0.033, wR = 0.034 for 5002 observed reflections.

Biological profile of 2-[4-(2-N-piperidinoethoxy) phenyl]-3-phenyl (2H) benzo (b) pyran--a potent antiimplantation agent in rat.

Compound CDRI-85/287: 2-[4-(2-N-piperidinoethoxy) phenyl]-3-phenyl (2H) benzo (b) pyran has been identified as a potent antiimplantation agent in rat. A single oral dose (2.5 mg/kg body weight) of the compound administered on days 1, 2 or 3 of pregnancy or multiple dosing (0.05 mg/kg daily) on days 5-7 postcoitum effectively prevented pregnancy. When administered on days 5-7 postcoitum, it failed to interrupt pregnancy even at 20 mg/kg dose. The compound is a potent antiestrogen, with very weak uterotrophic activity; it does not induce vaginal cornification in immature ovariectomised rat. Also, it is devoid of progestational, antiprogestational, androgenic, antiandrogenic and antigonadotrophic activities. The results suggest that the compound exerts its antiimplantation acivity in rat by virtue of its antiestrogenic activity [corrected].

Structure-activity relationship of antiestrogens. Studies on 2,3-diaryl-1-benzopyrans.

A series of 2,3-diaryl-1-benzopyran analogues substituted at position 4 of 2-phenyl with a hydroxy or pyrrolidinoethoxy residue were synthesized as models for (E)-triarylpropenones constrained in the s-trans conformation. The prototypes, belonging to five chemical series, were evaluated for their estrogen receptor affinity and for estrogen agonist-antagonist activities. The 4H-1-benzopyran-4-one, the 2,3-dihydro-4H-1-benzopyran-4-one, the 4H-1-benzopyran, and the 2,3-dihydro-1-benzopyran derivatives were found to be inactive or only marginally activate as receptor ligands or estrogen agonists-antagonists. In the 2H-1-benzopyran category the parent phenol was also inactive whereas the basic ethers 16 and 26 were modest receptor ligands while being quite active as antiestrogens. In a comparative study the benzopyran 16 was found to be more effective antiestrogen than tamoxifen while being as effective as LY-117018. The benzopyrans have thus emerged as a new class of potent antiestrogens.

Structure-activity relationship of antiestrogens. Effect of the side chain and its position on the activity of 2,3-diaryl-2H-1-benzopyrans.

A series of 2,3-diaryl-2H-1-benzopyrans carrying a tertiary aminoethoxy chain at the ortho, meta, or para position of 2-phenyl or an alkyl at position 4 of the pyran ring were synthesized and evaluated for their affinity for estrogen receptor (ER) and for microsomal antiestrogen specific binding site and for their uterotrophic-antiuterotrophic activities in rodents. The analogues bearing the side chain at the para position of 2-phenyl were found to be active while those substituted at the meta and ortho positions were inactive as ER ligands as well as estrogen agonists-antagonists. Among para-substituted ethers, the 2-piperidinoethoxy analogue 5 was found to be a more effective antiestrogen than the corresponding pyrrolidino, dimethylamino, and related analogues. Incorporation of a methyl or an ethyl at C4 in the pyran nucleus was found to increase receptor affinity of the prototypes. The ethyl was also found to potentiate agonist activity of the prototype while abolishing its antagonist activity. The piperidino analogue 5 was found to be a better antiestrogen than tamoxifen as well as LY-117018 in rats as well as mice. The prototypes were also found to have high affinity for the microsomal antiestrogen specific binding sites. The benzopyrans have thus emerged as a new group of potent antiestrogens.

Structure-activity relationship of antiestrogens. Phenolic analogues of 2,3-diaryl-2H-1-benzopyrans.

Phenolic analogues of 2-[4-(2-piperidinoethoxy)phenyl]-3-phenyl-2H-1-benzopyran (1), a novel antiestrogen, were synthesized and evaluated for their structure-activity relationship. Incorporation of OH at position 7 was found to improve receptor affinity of the benzopyran while having no effect on its action as an antagonist. Similar substitution of 2-phenyl as well potentiated receptor affinity as well as antagonist activity of the prototype. The monophenol 19 and the diphenol 25 were thus found to be good receptor ligands, devoid of estrogen agonist activity and associated with marked antiestrogenic activity of comparable order. Both caused nearly complete inhibition of the estradiol stimulated uterine growth in rats as well as mice and were thus found to be better antiestrogens than tamoxifen, trioxifen, and LY-117018. A binding-site model for estrogen receptor rationalizing the structure-activity relationship of benzopyrans in relation to that of the triarylethylene and the triarylpropenone antiestrogens has been discussed.

Structure-activity relationship of antiestrogens: a study using triarylbutenone, benzofuran, and triarylfuran analogues as models for triarylethylenes and triarylpropenones.

In a study of the structure-activity relationship (SAR) of antiestrogens use has been made of certain 1,2,3-triarylbutenones, of 2-arylbenzofurans carrying aryl or aroyl substituents at C3, and of 2,3,4-triarylfurans as conformationally constrained models for triarylethylene (TAE) and triarylpropenone (TAP) prototypes. The position-specific contributions of substituents to receptor affinity and to agonist-antagonist profiles were used as aids in characterizing the relative binding orientation of the prototypes. Although most compounds were found to be weak receptor ligands and poorly active in vivo, the following conclusions could be drawn about their SAR: (i) (Z)-TAPs and TAEs interact with the receptor in an analogous manner using the trans-stilbene core, with their agonist-antagonist profiles depending on the nature of other substructures. (ii) Incorporation into the benzofuran framework introduces a stereoelectronic constraint that compromises the normal binding interactions of TAE, as well as TAP, prototypes, resulting in their poor affinities and weak biological activities. (iii) (E)-TAPs can interact with the receptor through their S-cis conformation, but such a binding mode is unlikely to account for their behavior as antagonists.

New Cycloartenol Derivatives from Aglaia roxburghiana1.

Two triterpenes, isolated from the aerial parts of AGLAIA ROXBURGHIANA have been characterized as 29-nor-cycloartan-24,25-epoxy-3beta-ol and 29-nor-cycloartan-23-ene-3beta,25-diol; 29-nor-cycloartenol and 28,29-bis-nor-cycloartan-24-methylene-3beta,6alpha-diol, were also isolated.

Antiviral activity of (+)-odorinol1.

A phytochemical investigation of AGLAIA ROXBURGHIANA var. Beddomei (Meliaceae) resulted in the isolation of the active principle and its characterisation as (+)-odorinol exhibiting strong antiviral activity against Ranikhet disease virus (RVD) in chick embryo.

Structure-activity relationship of estrogens: receptor affinity and estrogen antagonist activity of certain (E)- and (Z)-1,2,3-triaryl-2-propen-1-ones.

(E)- and (Z)-1,2,3-triphenyl-2-propen-1-ones and some of their phenolic and alkoxy analogues, substituted at the para position in one or more of the aromatic rings, were synthesized and assigned geometry on the basis of their spectroscopic data. The structure-activity relationship of the triarylpropenones was studied from the point of view of their estrogen receptor affinity and estrogen agonist and antagonist activities. (E)- as well as (Z)-propenones were found to compete with estradiol for binding with the mouse uterine cytosol receptors, with phenolic analogues usually more potent than the unsubstituted as well as alkoxypropenones. The (E)-propenones, which have now emerged as a new group of estrogen receptor ligands, were found to differ from Z isomers quite markedly in their binding specificities. The uterotrophic and antiuterotrophic assays in immature mice revealed that while some of the compounds were marginally estrogenic, nearly all the isomeric propenones were antiestrogenic to a varying degree.

Cis isomer of centchroman--a selective ligand for the microsomal antiestrogen binding site.

Several compounds structurally related to the triarylethylene antiestrogens, but possessing weak estrogen receptor affinities, were assessed for their ability to interact with the microsomal antiestrogen binding site. While all the compounds tested did interact with this site their relative affinities were somewhat lower than that of tamoxifen. One of these, viz., the cis isomer of centchroman, has however emerged as a selective ligand for the antiestrogen binding site since its estrogen receptor affinity is nearly 50,000 times lower on a relative scale.

Structure-activity relationship of estrogens: a study involving cyclofenyl as the model compound.

Bis-(p-acetoxyphenyl)cyclohexylidenemethane [cyclofenyl] has been shown to resemble triarylethylene estrogens quite closely in its receptor binding specificity as well as activity profile. Mono-pyrrolidinoethyl ether of cyclofenyl thus acts as a more potent receptor binder but less potent estrogen than its parent. Like triarylethylene antiestrogens, this derivative of cyclofenyl also acts as an antiuterotrophic agent. This finding would substantiate the proposition that the geminal diaryl residue and not the 1,2-diarylethylene moiety is mainly responsible for the receptor binding and activity profile characteristic of triarylethylenes. This understanding can form a basis for the rationalization of the structure-activity-relationship of estrogens at the molecular level.