Total synthesis and biological activity of neopeltolide and analogues

Combining the core structure of neopeltolide, lactone 16 a, with the oxazole-containing side chain 23 via a Mitsunobu reaction provided the cytotoxic natural product neopeltolide (2). The side chain 23 was prepared from oxazolone 24 via the corresponding triflate. Key steps in the preparation of 23 were a Sonogashira coupling, an enamine alkylation, and a Still-Gennari Horner-Emmons reaction. By changing the Leighton reagent in the allylation step, the 11-epimer of lactone 16 a, compound 50 was prepared. This led to 11-epi-neopeltolide 51. The 5-epimer of neopeltolide, compound 52, could be obtained from the minor isomer of the Prins cyclization. Furthermore, a range of analogues with modifications in the side chain were prepared. All derivatives were checked for toxicity effects on mammalian cell cultures and inhibitory effects on NADH oxidation in submitochondrial particles of bovine heart. Modifications in the lactone part are tolerated to some degree. On the other hand, shortening the distance between the oxazole and the lactone causes a significant drop in activity. Analogue 65 with an additional double bond is equally or even more active than neopeltolide itself.     

Synthesis of C-2 substituted vitamin D derivatives having ringed side chains and their biological evaluation, especially biological effect on bone by modification at the C-2 position

In order to obtain vitamin D derivatives, which have strong activity for enhancing bone growth, we designed vitamin D derivatives with various substitutions at the C-2 position. Novel 2 α-substituted vitamin D derivatives were synthesized starting from d-glucose as a chiral template of the A-ring with a CD-ring bromoolefin unit using the Trost coupling method. We evaluated these compounds by two in vitro assays, affinity to VDR and transactivation assays, using human osteosarcoma (Hos) cells, and demonstrated the SAR of the C-2 position of VD(3). Furthermore, by using the OVX model, we found that compound 5c, which has a hydroxypropoxy side chain at C-2 and 2,2-dimethyl cyclopentanone in the CD-ring side chain, has a strong activity for enhancing bone growth, same as the reported compound, 2α-(3-hydroxypropoxy)-1α,25-dihydroxyvitamin D(3)1d, and this derivative shows a possibility that calcemic activity is less than 1d in vivo.     

Photoluminescent behavior of poly(3‐hexylthiophene) derivatives with a high azobenzene content in the side chains

A series of polythiophene derivatives with substantially higher azobenzene contents in the side chains were prepared via copolymerization of 3‐hexylthiophene with four different types of 4‐((4‐(phenyl)azo)phenoxy)alkyl‐3‐thienylacetate. The alkyl spacers with different lengths, i.e. butyl, hexyl, octyl and undecyl groups were used between the azobenzene group and the thiophene ring. The compositions, structures and thermal properties of these polythiophene derivatives were characterized. The structural dependence of photoluminescent emission, photochromic behavior of these copolymers were systematically studied and compared with poly(3‐hexylthiophene). The results show that the azobenzene substitution renders the polythiophene some interesting optical properties that can be modulated by UV light irradiation. In the azobenzene modified polythiophene, the intensity of photoluminescent emission associated with the conjugated polythiophene main chain was found to decrease significantly upon UV irradiation. The finding suggests that the photo‐induced trans‐cis isomerization of the azobenzene pendant groups has a significant effect on photoluminescent emission, particularly when short spacers are used between azobenzene groups and the main chain. However, the effect becomes less prominent when longer spacers are used between the azobenzene group and the main chain. Furthermore, UV irradiation of the copolymers also resulted in an increase in intensity and broadening of bandwidth for the absorption peak associated with the polythiophene backbones. Again the magnitude of intensity changes upon UV irradiation were found to be dependent on the spacer length between the azobenzene group and polythiophene main chain. Copyright © 2005 John Wiley & Sons, Ltd.     

6-s-cis locked analogues of the steroid hormone 1alpha, 25-dihydroxyvitamin D(3). Synthesis Of novel A-ring stereoisomeric 1, 25-dihydroxy-3-epi-19-nor-previtamin D(3) derivatives

Efficient syntheses of A-ring synthons 24 and 32 are described from hydroxy ester 16, which is easily available on a preparative scale from (-)-quinic acid. Key features of the syntheses were (a) the ability to selectively perform desilylations in the presence of p-nitrobenzoate esters and (b) the excellent yield and complete stereospecificity with which the configuration of alcohols 16, 18, and 26 could be inverted under Mitsunobu conditions. Thus, A-ring synthons 24 and 32 were both prepared in 35-38% yield (eight steps) from the common precursor 16. The coupling of A-ring synthons 24 and 32 with the appropriate CD-ring/side chain fragment 7 provides access to novel 6-s-cis locked analogues of steroid hormone 1alpha, 25-dihydroxyvitamin D(3): 1alpha, 25-dihydroxy-3-epi-19-nor-previtamin D(3) (37) and 1beta, 25-dihydroxy-3-epi-19-nor-previtamin D(3) (38), which are unable to undergo rearrangement to the respective vitamin D form by virtue of the absence of the C-19 methyl group. Compounds 37 and 38 can be used as tools for studying the genomic and nongenomic mechanisms of action of the previtamin form of the hormone 1alpha, 25-dihydroxyvitamin D(3).     

Synthesis of (-)-calicoferol B

The first total synthesis of (-)-calicoferol B (III) is described. The cyclozirconation product I, prepared in enantiomerically pure form, was converted into the CD ring chiron II. This was coupled with the aromatic A-ring, and then the side chain was constructed with control of relative and absolute configuration to complete the total synthesis of III. The first total synthesis of (-)-calicoferol B (1) is described. The cyclozirconation product 8, prepared in enantiomerically pure form, was converted into the CD ring chiron 6. This was coupled with the aromatic A-ring, and then the side chain was constructed with control of relative and absolute configuration to complete the total synthesis of 1.     

Function Oriented Synthesis: Preparation and Initial Biological Evaluation of New A-Ring-Modified Bryologs

The synthesis and biological evaluation of the first members of a new series of designed bryostatin A-ring analogues (bryologs) are described. An advanced intermediate is produced that allows for step economical access to diverse analogs. The first of these analogues, bearing side chains of completely different polarities from alkyl to hydroxyl and carboxyl functionalities, were evaluated. All exhibit potent protein kinase C binding (54.7-2.4 nM) with affinities increasing with decreasing side chain polarity. This series of bryostatin analogues demonstrates that A-ring surrogates can indeed be used for tuning pharmacophore and ADME characteristics as needed to improve bryolog function.     

Synthesis and antitumor activity of 20(S)-camptothecin derivatives: A-ring modified and 7,10-disubstituted camptothecins.

20(S)-Camptothecin derivatives having nitro, amino, chloro, bromo, hydroxyl and methoxyl groups in the A-ring were synthesized. B-Ring hydrogenated camptothecin (2a) was converted into 10-hydroxycamptothecin (6e) by treatment with lead tetraacetate in trifluoroacetic acid. 10-Substituted derivatives (6) were obtained by a photoreaction of N-oxides (9). The cytotoxicity of the A-ring modified camptothecins was evaluated against KB cells in vitro and leukemia L1210 in mice. 7-Ethyl-10-hydroxycamptothecin (6i) was identified as a potential derivative for further modification.     

Synthesis and biological evaluation of all A-ring stereoisomers of 5,6-trans-2-methyl-1,25-dihydroxyvitamin D(3) and their 20-epimers: possible binding modes of potent A-ring analogues to vitamin D receptor.

BACKGROUND: The secosteroid 1 alpha,25-dihydroxyvitamin D(3) (1) has a wide variety of biological activities, which makes it a promising therapeutic agent for the treatment of cancer, psoriasis and osteoporosis. Insight into the structure-activity relationships of the A-ring of 1 is still needed to assist the development of more potent and selective analogues as candidate chemotherapeutic agents, as well as to define the molecular mode of action. RESULTS: All possible A-ring stereoisomers of 5,6-trans-2-methyl-1,25-dihydroxyvitamin D(3) (6a-h) and their 20-epimers (7a-h) were designed and efficiently synthesized. The dependence of the affinities for vitamin D receptor (VDR) and vitamin D binding protein (DBP), as well as the HL-60 cell differentiation-inducing activity, upon the stereochemistry of the A-ring and at C20 in the side chain was evaluated. CONCLUSIONS: The binding affinities and potency of the 5,6-trans and 5,6-cis analogues were enhanced by a 2-methyl substituent in a certain orientation. Molecular docking studies based upon the X-ray crystal structure of VDR suggested that the axial 2-methyl group would be accommodated in a pocket surrounded by hydrophobic amino acid residues in the ligand binding domain, resulting in enhanced interaction.     

Solid-phase synthesis of phenolic steroids: from optimization studies to a convenient procedure for combinatorial synthesis of biologically relevant estradiol derivatives

During the course of our studies on therapeutic agents for the treatment of breast cancer, we became interested in the solid-phase combinatorial synthesis of estradiol derivatives that contain a functionalized side chain at either position 16 beta or 7 alpha. Both types of compounds have already demonstrated inhibitory activity toward both biosynthesis and action of estradiol. As a first step, two versatile precursors bearing an azidoalkyl side chain at either position 16 beta or 7 alpha of estradiol were synthesized using standard solution-phase methods. Afterward, the effectiveness of five linkers to attach the phenolic function of these estradiol derivatives to a polystyrene resin was investigated; they were benzylic ether (Merrifield), 4-alkoxy-benzylic ethers (Wang, Sheppard), tetrahydropyranyl ether (Ellman), benzoic ester, and o-nitrobenzyl ether. To test the linker in a synthetic context, a short sequence of reactions, including reduction of the azide and acylation of the corresponding amine, was performed on the polymer-bound estradiol derivative. While all of the tested linkers proved effective in attaching the phenol functionality of the precursor, only the o-nitrobenzyl ether photolabile linker enabled the release of the final products in acceptable purities. Consequently, this linker was used to perform successfully the solid-phase synthesis of four different classes of estradiol derivatives in acceptable yields and excellent purities. This study was preliminary to the combinatorial synthesis of larger libraries of biologically relevant estradiol derivatives.     

Preparation of benzene, furan, and thiophene analogs of duocarmycin SA employing a newly-devised phenol-forming reaction

Five A-ring analogs of duocarmycin SA 9a-e were synthesized in racemic form modifying our second synthetic route toward duocarmycin SA. The problem encountered at the crucial phenol forming step to secure 17a, b from 16a, b under the conventionally used Kuwajima conditions was overcome by devising a more convenient method: simple heating of 16a-c in benzene in the presence of bis(triphenylphosphine)palladium(II) chloride (10 mol%), cesium carbonate (3 eq), and triphenylphosphine (0.3 eq) gave 17a-c in high yields of 86-91%. The intermediates 17a-e were readily led to the A-ring analogs (+/-)-9a-e almost according to the reported route.     

Studies toward the total synthesis of armatol F: stereoselective construction of the C6 and C7 stereocenters and formation of the A-ring skeleton

Armatol F, isolated from the red alga Chondria armata as a polyether triterpene, has a solitary oxepane (A-ring) and a fused tricyclic ether moiety (BCD-ring). The A-ring features a rare cis-relationship between the hydroxy group at the quaternary carbon C6 and the carbon chain at C7. As part of our program toward the total synthesis of armatol F, a new stereoselective method for the construction of the C6 and C7 stereocenters has been developed based on chirality-transferring Ireland-Claisen rearrangement. The A-ring skeleton has also been synthesized from the rearrangement product by a process including ring-closing olefin metathesis.     

Structure-odor relationships of α-santalol derivatives with modified side chains

(Z)-α-Santalol, which has a unique woody odor, is a main constituent of sandalwood essential oil. We investigated the structure-odor relationship of (Z)-α-santalol and its derivatives, focusing on the relationship between the structure of the side chain and the odor of the compounds. Various α-santalol derivatives (aldehydes, formates, and acetates) were synthesized from (Z)- and (E)-α-santalol, which were prepared from (+)-3-bromocamphor through modifications of a reported synthetic route. The Z- and E-isomers of α-santalols have different double-bond configurations in the side chain. Analogues with saturated side chains were also prepared from the corresponding α-santalols, and the odors of the all the prepared compounds were evaluated. We found that the odors of the Z-isomers (woody) were similar to those of the corresponding saturated compounds, but clearly different from the odors of the corresponding E-isomers (odorless, fresh, or fatty). These results indicate that the relative configuration of the side chain with respect to the santalane frame plays an important role in the odor of α-santalol. E-configuration in the side chain eliminates the woody odor character of α-santalol and its examined derivatives, whereas the Z-configuration or saturation of the carbon side chain does not.     

Structure-activity relationships of sandalwood odorants: synthesis of a new campholene derivative

Structural modifications of natural (-)-(Z)-beta-santalol have shown that the sandalwood odor impression is highly sensitive, even to small structural changes. Particularly, the substitution of the quaternary carbon is of great influence on the scent. Epi-compounds with side chains in the endo-position possess sandalwood odor in only a few derivatives, whereas modifications at this side chain, as well as modification at the bicyclic ring systems mostly lead to a complete loss of sandalwood fragrance.     

Triterpene glycosides from <Emphasis Type="Italic">Astragalus</Emphasis> and their genins. LXXXVII. Chemical transformation of cycloartanes. IX. Partial synthesis of cycloasalgenin

The natural cycloartane triterpenoid cycloasalgenin, which is 20R,24S-epoxycycloartan-3β,6α,25-triol16-one, was partially synthesized in three steps starting from cyclosiversigenin. In addition to the desired product, its 17-epimer was synthesized. The analogous 17-epimer was also prepared from cycloadsurgenin.     

The binding of human carbonic anhydrase II by functionalized folded polypeptide receptors

Several receptors for human carbonic anhydrase II (HCAII) have been prepared by covalently attaching benzenesulfonamide carboxylates via aliphatic aminocarboxylic acid spacers of variable length to the side chain of a lysine residue in a designed 42 residue helix-loop-helix motif. The sulfonamide group binds to the active site zinc ion of human carbonic anhydrase II located in a 15 A deep cleft. The dissociation constants of the receptor-HCAII complexes were found to be in the range from low micromolar to better than 20 nM, with the lowest affinities found for spacers with less than five methylene groups and the highest affinity found for the spacer with seven methylene groups. The results suggest that the binding is a cooperative event in which both the sulfonamide residue and the helix-loop-helix motif contribute to the overall affinity.     

Functional monomers and polymers. CIV. Synthesis and properties of oligomer models of polyethyleneimine derivatives with spacer-separated nucleic acid bases

A series of polyethyleneimine derivatives and their oligomer models with pendant thymine or adenine bases separated by β-alanyl groups as spacers were prepared by an activated ester method. To elucidate the nature of intramolecular interaction of thymine and adenine bases ultraviolet (UV) spectrophotometric studies were undertaken for the series of compounds and the results were compared with those obtained for the corresponding oligomers without spacers. In the thymine derivatives, the nature of the intramolecular interaction resembled that of the corresponding compounds without β-alanyl units, although larger hypochromicities were found in the series with β-alanyl units. In the adenine derivatives, contrary to the corresponding thymine systems, UV hypochromicities of the compounds decreased by incorporation of the spacer group into side chains. It became evident that the intramolecular interaction of adenine bases was due to stacking neutral species, hydrogen bonding, and residual hypochromicity for the protonated species.     

Effects of Spacers on Photoinduced Reversible Solid-to-Liquid Transitions of Azobenzene-Containing Polymers

Photoisomerization in some azobenzene-containing polymers (azopolymers) results in reversible solid-to-liquid transitions because trans- and cis-azopolymers have different glass transition temperatures. This property enables photoinduced healing and processing of azopolymers with high spatiotemporal resolution. However, a general lack of knowledge about the influence of the polymer structure on photoinduced reversible solid-to-liquid transitions hinders the design of such novel polymers. Herein, the synthesis and photoresponsive behavior of new azopolymers with different lengths of spacers between the polymer backbone and the azobenzene group on the side chain are reported. Azopolymers with no and 20 methylene spacers did not show photoinduced solid-to-liquid transitions. Azopolymers with 6 or 12 methylene spacers showed photoinduced solid-to-liquid transitions. This study demonstrates that spacers are essential for azopolymers with photoinduced reversible solid-to-liquid transitions, and thus, gives an insight into how to design azopolymers for photoinduced healing and processing.     

棒丝氨酸的全合成研究I. 从D-葡萄糖合成3-[3'R, 5'S)-7'-氧代-1'-氮杂-4'-氧杂双环[3.2.0]-庚-3'-基]-3-O-苄基-(2S, 3S)-丝氨酸及其(3'R, 5'R)-差向异构体

以D-葡萄糖为原料经侧链氨基酸合成, 与β-内酰胺缩合, 唑烷环合和除保护基等反应合成了棒丝氨酸的O-苄基衍生物, 3-[3'R, 5'S)-7'-氧代-1'-氮杂-4'-氧杂双环[3.2.0]-庚-3'-基]-3-O-苄基-(2S, 3S)-丝氨酸及其(3'R, 5'R)-差向异构体(18)。     

Synthesis and activity of largazole analogues with linker and macrocycle modification

To characterize largazole's structural requirements for histone deacetylase (HDAC) inhibitory and antiproliferative activities, a series of analogues with modifications to the side chain or 16-membered macrocycle were prepared and biologically evaluated. Structure-activity relationships suggested that the four-atom linker between the macrocycle and octanoyl group in the side chain and the (S)-configuration at the C17 position are critical to repression of HDAC activity. However, the valine residue in the macrocycle can be replaced with alanine without significant loss of activity.     

A synthetic approach toward nitiol: construction of two 1,22-dihydroxynitianes

Synthetic work toward the total synthesis of nitiol has culminated in the construction of two epimeric hydroxylated derivatives, the 1,22-dihydroxynitianes. Key stereodefining steps in the construction of the A-ring fragment (13) were the use of a siloxy-epoxide rearrangement reaction, a Pauson-Khand reaction, a Norrish 1 photochemical cleavage reaction, and a highly regio- and stereoselective hydrostannylation reaction of an ynoate. The stereochemistry of the synthetically challenging C-ring fragment (20) was established using an Ireland-Claisen reaction and a Grubbs ring-closing metathesis process as key steps. The 12-membered B-ring of the nitiane skeleton was constructed using a copper-promoted Stille cross-coupling and a Kishi-Hiyama-Nozaki carbonyl addition reaction. Unfortunately, the carbonyl addition reaction produced hydroxyl functionality that could not be selectively removed. Consequently, a synthesis of epimeric 1,22-dihydroxynitianes, which are compounds that are structural hybrids of two natural products, nitiol and variculanol, was completed.