Seco Derivatives Research Articles

New oxidative decomposition mechanism of estradiol through the structural characterization of a minute impurity and its degradants

Herein we discuss the structure elucidation of a labile estradiol-related degradant, X1. X1 was detected at Gedeon Richter as an unknown trace impurity in a pharmaceutical formulation containing estradiol (1a) and norethisterone acetate (NA) as active ingredients. The structural identification of X1 proved to be an unusually complex task involving an initial structural hypothesis based on some limited analytical data (UV) obtained from the formulation, synthetic work targeting the proposed structure, chromatographic enrichment from the synthetic reaction mixture, (HPLC)–MS and MS–MS studies of the formulation and of samples from the synthesis using almost all available ionization modes, preparative LC enrichment, and the complementary use of off-line and on-line NMR techniques. Based on these results, X1 was finally characterized as a new oxidative product of estradiol, containing an epoxy function over the C9–C10 bond. During the structure determination of X1 its secondary and tertiary decomposition products were also identified as a new secoepoxy (6) and a known seco derivative (5a) of estradiol, respectively. On this basis a new oxidative decomposition mechanism of estradiol and its analogues could be proposed. A generalization of the mechanism of this pathway can more readily explain the formation of some oxidative secosteroid degradants than the mechanism proposed earlier in the literature.

Plakortolide Stereochemistry Revisited: The Checkered History of Plakortolides E and I

The relative configuration of the plakortolide metabolite (4) isolated from a Madagascan Plakortis sp. and named (+)-plakortolide I is revised following reassignment of the ¹³C signals for C-7 and C-16, thereby establishing that the metabolite isolated was likely (+)-plakortolide E (3). We propose that the name "plakortolide I" should be retained for the plakortolide metabolite 5 first isolated by the Faulkner group; its enantiomer 4 can then be named ent-plakortolide I in line with the description of Barnych and Vatèle. The spectroscopic data for MPA esters prepared from synthetic samples of seco derivatives of plakortolide E (3) and ent-plakortolide I (4) were compared with those of MPA esters of seco derivatives from naturally isolated plakortolides L (1) and K (2) and of seco-plakortolide E (6a). Likewise, the spectroscopic data for MTPA esters derived from 3 and 4 were compared with data for the MTPA esters derived from 5. These various comparisons established that the sign of the specific rotation associated with the natural isolates is an unreliable indicator of absolute configuration and verify that the absolute configurations of plakortolides L (1), K (2), E (3), and I (5) are (3S, 4S, 6S), (3R, 4R, 6S), (3R, 4R, 6R), and (3S, 4S, 6R), respectively.

Novel Silicon‐Based Patchouli Odorants of the Trialkyl(1‐hydroxy‐1‐methylethyl)silane Type: Design, Synthesis, and Olfactory Properties

tert-Butyl(1-hydroxy-1-methylethyl)dimethylsilane (5), a sila-substituted seco derivative of the recently reported patchouli lead structure (4aR*,8aR*)-1,1,8a-trimethyldecahydronaphthalene-4a-ol (4), and a number of related trialkyl(1-hydroxy-1-methylethyl)silanes and further derivatives, compounds 8-24, with different silicon-bound substituents (Me, Et, iPr, cPr, tBu, iBu, cPent, vinyl, SiMe(3)) were synthesized and studied for their olfactory properties. All of the silanes studied exhibit at least one of the main patchouli odor descriptors 'woody,' 'earthy,' and 'camphoraceous,' and some even exhibit all of them. The silanes MeR(2)SiC(OH)Me(2) (12) and R(3)SiC(OH)Me(2) (14) (R=cyclopropyl) were found to resemble natural patchouli oil most closely, with an even lower odor threshold than the natural lead structure (-)-patchoulol (1). To complete this structure-odor relationship study, the carbon analogues of 12 and 14 (Si/C exchange) were also prepared and characterized. Although they show similar olfactory properties to the silanes 12 and 14, the synthesis of the corresponding carbon analogues is far less straightforward than that of the silicon compounds, and only silanes 12 and 14 can be economically produced industrially.

Synthesis and evaluation of A- seco type triterpenoids for anti-HIV-1protease activity

2,3- Seco-dioic acids derived from four different triterpene skeletons were prepared and evaluated for their anti-HIV-1 protease activity. Two A- seco derivatives showed potent inhibitory activity against HIV-1 protease ( 3c and 3e, IC 50 5.7 and 3.9 μM, respectively), while four other derivatives showed moderate to weak inhibition ( 3a, 3b, 3d and 3f, IC 50 15.7–88.1 μM). The combination of a 2,3- seco-2,3-dioic acid functional group in ring A and a free acid group at C-28 or C-30 significantly enhanced HIV-1 protease inhibitory activity ( 3a, 3c– 3e, IC 50 3.9–17.6 μM). On the other hand, all A- seco derivatives were found to be very weak inhibitors of HCV, renin and trypsin proteases (IC 50 > 80 μM). These findings indicate that A- seco triterpenes with a carboxyl group at C-28 or C-30 are novel and highly selective HIV-1 protease inhibitors.

Biological activities of lignoids from Amazon Myristicaceae species: Virola michelii, V. mollissima, V. pavonis and Iryanthera juruensis

This work revisits the fruits of Iryanthera juruensis and Virola pavonis and the leaves from V. michelii, as well as describing a study of the fruits of V. mollissima. In I. juruensis aryltetraline neolignan (1) and tetrahydrofuran neolignan (2), were found while from V. pavonis neolignans of benzofuran type (6-9), the tetrahydrofuran type (2, 11-13, 17) and the biphenyl type (10), in addition to diastereoisomers of the 8.O.4'-oxyneolignan type (14 and 15) and others were isolated. The V. mollissima accumulates the aryltetralone neolignan 4 and its seco derivative (5). The lignoids 1 and 2 obtained from I. juruensis arils possess antileishmanial activity against the promastigote form of Leishmania amazonensis.

Synthesis and biological evaluation of bengacarboline derivatives

Novel derivatives of the marine alkaloid bengacarboline have been synthesized. The seco derivatives 11 and 12 were evaluated for topoisomerase inhibition, DNA damages, cytotoxicity and cell cycle perturbation. The two synthetic analogs are more potent cytotoxic agents than bengacarboline and they both induce an accumulation of cells in the S phase of DNA synthesis. They do not function as topoisomerase inhibitors but trigger DNA damages in cells.

Synthesis of A-seco derivatives of betulinic acid with cytotoxic activity.

In this study, the relationships between the chemical structure and cytotoxic activity of betulinic acid (1) derivatives were investigated. Eight lupane derivatives (1-8), one of them new (6), five diosphenols (9-13), four of them new (10-13), two new norderivatives (14 and 15), five seco derivatives (16-20), four of them new (16, 17, 19, and 20), and three new seco-anhydrides (21-23) were synthesized from 1, and their activities were compared with the activities of known compounds. The effects of substitution on the A-ring and esterification of the carboxyl group in position 28 on cytotoxicity were of special interest. Significant cytotoxic activity against the T-lymphoblastic leukemia cell line CEM was found in diosphenols 9 and 13 (TCS(50) 4 and 5 micromol/L) and seco-anhydrides 22 and 23 (TCS(50) 7 and 6 micromol/L). All compounds were also tested on cancer cell lines HT 29, K562, K562 Tax, and PC-3, and these confirmed activity of diosphenols 9, 10, and 11 and anhydride 22. Diosphenols, as the most promising group of derivatives, were further tested on four more lines (A 549, DU 145, MCF 7, SK-Mel2).

Synthesis and reactions of aminoporphyrazines with annulated five- and seven-membered rings.

The novel five- and seven-membered ring appended aminoporphyrazines 3 and 12 have been prepared via mixed Linstead macrocyclization. The structures of both have been unequivocally established by X-ray crystallographic studies. Reductive deselenation of selenadiazole 3 in the presence of 9,10-phenanthrenequinone or 2,3-butanedione results in the formation of pyrazines 6a,b, whereas oxidation of porphyrazine 12 gave the corresponding seco derivative 14. seco-Porphyrazine 14 mediates the generation of singlet oxygen with a quantum yield of 0.74.

Ergosteroids V: preparation and biological activity of various D-ring derivatives in the 7-oxo-dehydroepiandrosterone series.

Our previous finding that D-ring seco derivatives of dehydroepiandrosterone retained biologic activity (Reich et al., Steroids 1998;63:542-53) motivated us to synthesize and test a number of steroids in which the D-ring is retained but altered in various ways. Several new steroids were synthesized and characterized by (1)H and (13)C NMR spectroscopy. The availability of a number of closely related compounds allowed detailed (13)C chemical shift correlations. Using the induction of two thermogenic enzymes in rats, liver mitochondrial glycerophosphate dehydrogenase (GPDH) and cytosolic malic enzyme, as criteria of biologic activity some 30 compounds were assayed. Hydroxylation of dehydroepiandrosterone (DHEA) at the 16 alpha position was previously shown to diminish activity (Lardy et al., Steroids 1998;63:158-65); the corresponding 7-oxo compound is fully active. Hydroxylation at the 15 beta position of DHEA, 7-oxo-DHEA, or 16 alpha-hydroxy-7-oxo-DHEA greatly diminished the induction of GPDH but induction of malic enzyme was retained. Most 5,15 diene steroids tested had 2 weak, or no, ability to enhance the formation of GPDH but did increase malic enzyme.

The synthesis of two diastereomeric seco-rhazinilams with opposite atropomeric chiralities

(−)-Tabersonine 4 was submitted to quaternization and Emde degradation to yield the 3,4- seco derivative 5, which was hydrolyzed and decarboxylated to the diastereomeric indolenines 8 and 9. Oxidative rearrangement of 8 and 9 yielded the two diastereomeric seco-rhazinilams (−)- 10 and (+)- 11, differing in the atropomeric conformations of their biarylic system. The results are discussed in the realm of oxidation and rearrangements in the aspidosperma series of indole alkaloids.

Valparane, a new diterpene skeleton (part iv). Absolute stereochemistry of valparone, valparolone and other compounds with valparane skeleton

The unsaponificable part of the hexane extract of Halimium viscosum chemotype (Valparaíso, Zamora, Spain) afforded three hydrocarbons, an epoxide, a ketone (valparone), five allylic alcohols and a seco derivative with valparane skeleton and an α,β-unsaturated ketone with valparolane skeleton. The majority of them have been correlated chemically. Chemical correlation between valparanes and valparolanes, absolute stereochemistry determined by means of CD for valparone and the confirmation of the absolute stereochemistry of valparanic and valparolanic compounds have been done by CD curve of the cyclohexanone obtained from valparolone.

Synthesis of Erythrina and Related Alkaloids. Part XXXV. Studies toward Total Synthesis of Non-aromatic Erythrina Alkaloids.(5). Cyclization of Perhydro-2-epoxymethylene-6-oxo-6H-pyrido(2,1-i)indole-1-acetic Acid: Synthesis of 8-Oxoerythroidans.

Treatment of the epoxy-acid (7) with acidic reagents produced a variety of products, hydroxy-γ- and δ-lactones (8 and 9), unsaturated δ-lactones (10, 11, and 18), and seco derivatives (15 and 17), depending on the reagents used. Alkaline hydrolysis of the hydroxy-γ-lactone (8) followed by acidification yielded an isomeric δ-lactone 21, which on further contact with acid regenerated the γ-lactone (8). The hydroxy-δ-lactones, 9 and 21, were stereoselectively dehydrated with thionyl chloride-pyridine to the unsaturated lactones, 18 and 10, respectively. Thus, successive treatments of the epoxy-acid (7) with NaOH, acidification, and dehydration of the product with thionyl chloride-pyridine gave 10 in an overall yield of 86%, and 10 was isomerized to the conjugated lactone (22) on treatment with 1, 8-diazabicyclo[5.4.0]undec-7-ene. For the above unsaturated δ-lactones, 22, 10, 11, and 18, the names α-, β-, γ-, and δ-erythroidans are proposed, respectively.

Photolyses and pyrolyses of triterpenoid nitrites

Derivatives of 19β,28-epoxy-18α-oleanane and lupane with nitrosyloxy group in positions 1α, 2β, 3α, 3β and 28 (II, V, VIII, X and XXVII, respectively) were subjected to photolysis in solution and in the crystalline state, as well as to pyrolysis. In most cases the products identified were alcohols, ketones, olefins and seco derivatives. Photolysis of 2β-nitrile V in benzene afforded the known 24- and 25-oximino derivatives XV and XVII, photolysis of 1α-nitrite II in the crystalline state led to the little stable form XIX of N-hydroxylactam XXI which in solution was easily converted into the derivative of O-acyl-N-alkylhydroxylamine XXII. Photolysis of crystalline 3β,28-lupanediyl 3-acetate, 28-nitrite XXVII gave 28-norolefins XXX and XXXI and 13β,28-epoxy derivative XXXII.

ChemInform Abstract: Steroids. Part 40. 15‐(Hydroxymethyl)androstene and ‐estratriene Derivatives.

AbstractThe reduction of the steroid (Ib) gives two isomers (III) and the seco derivative (IV).

Transformation products of furoeremophilanes and other constituents from Euryops arabicus

The aerial parts of Euryops arabicus afforded in addition to several known furoeremophilanes four new ones as well as four eremophilanolides, two seco derivatives and a rearranged spiro lactone. Furthermore two quercetin derivatives and an unusual diester of glucose were present. The structures were elucidated by high field NMR techniques and the biosynthesis of the unusual compounds is discussed.

Solution conformations of some acyclo nucleoside and nucleotide analogues of antiviral acyclonucleosides, and their substrate/inhibitor properties in several enzyme systems.

Chemical and enzymatic procedures have been employed for the preparation of various phosphorylated derivatives of the acyclonucleoside 9-(1,3-dihydroxy-2-propoxymethyl)adenine, an analogue of the active antiviral agent 9-(1,3-dihydroxy-2-propoxymethyl)guanine (DHPG). In combination with the previously reported 2',3'-seco nucleosides and their phosphates and cyclic phosphates (Stolarski et al., Z. Naturforsch. 41c, 758-770, 1986), this made available a broad class of acyclonucleosides and nucleotides, the acyclic moieties of which are capable of mimicking the ribose and 2'-deoxyribose rings. The solution conformations of the foregoing were determined with the aid of 1H, 13C and 31P NMR, and compared with those of DHPG and 9-(hydroxyethoxymethyl)guanine (Acyclovir, ACV). Particular attention was devoted to conformations about C-O bonds in different acyclic fragments, which demonstrated well-defined differences between 2',3'-seco derivatives on the one hand (conformational "rigidity") and derivatives with DHP and AC acyclic chains on the other (rotation about the C(1')-O(4') bond). The overall results are in good general agreement with reported crystal structures, and are compared with those obtained by quantum mechanical calculations. The conformational features of the various compounds are also discussed in relation to their substrate and/or inhibitor properties in a number of enzyme systems, including adenosine deaminase, phosphodiesterases, nuclease P1,3'-nucleotidase and herpes virus type 1 thymidine kinase.

ChemInform Abstract: Directed Alkyl Substitution of the Dodecahedrane Nucleus. The 1,4‐Dimethyl, 1,6‐Dimethyl, and 1,4,16‐Trimethyl Derivatives. Indanododecahedrane by Stepwise Dehydrogenation of a Benzylated Seco Derivative.

ChemInform Abstract: Directed Alkyl Substitution of the Dodecahedrane Nucleus. The 1,4‐Dimethyl, 1,6‐Dimethyl, and 1,4,16‐Trimethyl Derivatives. Indanododecahedrane by Stepwise Dehydrogenation of a Benzylated Seco Derivative.

Directed alkyl substitution of the dodecahedrane nucleus. The 1,4-dimethyl, 1,6-dimethyl, and 1,4,16-trimethyl derivatives. Indanododecahedrane by stepwise dehydrogenation of a benzylated seco derivative

Directed alkyl substitution of the dodecahedrane nucleus. The 1,4-dimethyl, 1,6-dimethyl, and 1,4,16-trimethyl derivatives. Indanododecahedrane by stepwise dehydrogenation of a benzylated seco derivative

Cecropiacic acid, a new pentacyclic A-ring seco triterpenoid from [formula omitted][formula omitted

From the methylated polar extract of stem bark of Musanga cecropioides (Cecropiaceae) a novel triterpenic A-ring seco derivative has been obtained and the structure elucidated by spectroscopic methods.

From penicillin to penem and carbapenem. VII. Synthesis and antibacterial activity of penem derivatives.

The azetidinone derivative (6), which has an (R)-hydroxyethyl substituent at the C-3 position, was prepared efficiently from 6-aminopenicillanic acid. From the dibromo seco derivative (10), compounds of the same type (16 and 17), but in dl-form, were obtained. Compounds 6 and 16 were reacted with various thiocarboxylic acids to obtain the penem derivatives (23a-n).The minimum inhibitory concentration values of these penems against various microorganisms were, determined, and the structure-activity relationship is discussed.