The multicomponent reactions and their libraries for natural and preparative chemistry.

It was recently recognized that three different types of multi-component reactions (MCRs) exist. In preparative chemistry, the MCRs of type II form their products particularly efficiently. These reactions correspond to equilibria of educts and intermediate products, whose final products are formed practically irreversibly. In recent years, the four component reaction of the isocyanides (U-4CR) of type II and their unions with various reactions and MCRs have become an important industrial process for preparing products and their libraries. It has been demonstrated that all conceivable collections of U-4CR educts can be converted into the corresponding products. In the usual chemical reactions, only the substituents of the products can be varied, whereas the U-4CR and related reactions can also produce skeletally different types of products with diverse substituents. The preparative advantages of forming products by the one-pot MCRs and the great variety of the possible products are illustrated in this review.

Formation of 1,1'-iminodicarboxylic acid derivatives, 2,6-diketo-piperazine and dibenzodiazocine-2,6-dione by variations of multicomponent reactions.

The combination of multicomponent reactions (MCRs) of different amino acids, aldehydes, isocyanides and acids allows complex structures to be prepared in one-pot reactions. The synthesis of 1,1'-iminodicarboxylic acid derivatives 12 demonstrates the high selectivity of the Ugi Four Component Reaction using two different aldehydes and two different isocyanides. The limitations of the MCRs are illustrated by the synthesis of a 1,1'-iminodicarboxylic acid derivative 6 from L-lysine. Furthermore, 2,6-diketopiperazines and dibenzodiazocin-2,6-diones are synthesized via MCRs.

Multicomponent Reactions with Isocyanides.

Multicomponent reactions (MCRs) are fundamentally different from two-component reactions in several aspects. Among the MCRs, those with isocyanides have developed into popular organic-chemical reactions in the pharmaceutical industry for the preparation of compound libraries of low-molecular druglike compounds. With a small set of starting materials, very large libraries can be built up within a short time, which can then be used for research on medicinal substances. Due to the intensive research of the last few years, many new backbone types have become accessible. MCRs are also increasingly being employed in the total synthesis of natural products. MCRs and especially MCRs with isocyanides offer many opportunities to attain new reactions and basic structures. However, this requires that the chemist learns the "language" of MCRs, something that this review wishes to stimulate.

[A 44-year-old patient with cardial carcinoma and paraneoplastic orbital disease]. / 44jähriger Patient mit Kardiakarzinom und paraneoplastischer Orbitopathie.

HISTORY AND CLINICAL FINDINGS: Bilateral orbital involvement with chemosis, protrusion and reduced vision developed in a 44-year-old man 12 weeks after carcinoma of the cardia with lymph node metastases and peritoneal carcinomatosis had been diagnosed and palliative chemotherapy with a cycle of leucovorin and 5-fluorouracil had been concluded. INVESTIGATIONS: Computed tomography excluded a retrobulbar metastasis. Thyroid hormone concentration was normal as was the thyroid autoantibody titre. There was also no evidence on sonography of endocrine orbital disease. These findings established the diagnosis of paraneoplastic orbital myositis. TREATMENT AND COURSE: The symptoms briefly regressed on initial treatment with systemically administered high doses of corticosteroids. Renewed marked eyeball protrusion with incipient visual loss was treated with conjunctival drainage and tarsorrhaphy, as well as radiotherapy to the retrobulbar space. This achieved significant improvement. Shortly thereafter the patients died of acute bleeding from the primary tumour. CONCLUSION: In patients with an underlying malignancy and symptoms of orbital myositis orbital involvement as part of a paraneoplastic syndrome should be diagnosed once other causes have been excluded.

[Melanoma-associated retinopathy with night blindness. Case report]. / Melanom-assoziierte Retinopathie (MAR) mit Nachtblindheit. Fallbericht.

BACKGROUND: Night blindness is usually symptomatic of retinal dysfunction. However, apart from congenital forms of night blindness such as congenital stationary night blindness (CSNB) and pigmentary retinopathy without clumping of pigment, the acquired forms of night blindness present a particular diagnostic challenge to the ophthalmologist. CASE REPORT: A 51-year-old patient with formerly healthy eyes presented with malignant skin melanoma and sudden night blindness. Along with reduced acuity, concentric visual field limitation, and a marked decrease in sensitivity of the retinal rods and cones in adaptometrical tests, significantly reduced b waves and intact a waves were registered in the flash-ERG of both eyes with otherwise inconspicuous morphologic findings. Furthermore, serum levels of antibodies (IgG) against retinal bipolar cells were found to be increased. CONCLUSION: Results indicate the presence of melanoma-associated retinopathy (MAR), which-like carcinoma-associated retinopathy (CAR)-ranks among the tumor-associated diseases of the retina. CAR, MAR, and CSNB can be differentiated immunohistochemically by serum autoantibody determination and electrophysiologically by flash-ERG. As opposed to CAR, the immune response in the case of MAR is not to antigens of photoreceptors and ganglion cells, but to retinal so-called ON-depolarizing bipolar cells mainly connected in series to the rods. In addition, a waves are intact and b waves extinct, resembling the situation of CSNB.

Facile syntheses of C2-symmetrical HIV-1 protease inhibitors.

With the goal of obtaining inexpensive yet potent anti-AIDS drugs, simple inhibitors of HIV-1 protease were synthesised. The C2-symmetrical pseudopeptidic substrate analogues can be prepared as inhibitors for HIV-1 protease starting from symmetrical ketones 3a-d by a facile four-step synthesis. After bromination of 3a-d to alpha,alpha'-dibromoketones 4a-d, we synthesised the diamino compounds 6a-c by Gabriel synthesis, which were then coupled with Z-valine to yield inhibitors including a central hydroxy group 8a-d a-i by azidation, reduction with LiAlH4 and coupling of the beta,beta'-diaminohydroxy compounds with appropriate peptides. The first set of compounds showed only weak inhibition whereas the latter reach Ki values of up to 3.0 microM.

Specific interaction between HIV-1 proteinase and 5'-phosphate peptidomimetic derivatives of nucleoside analogues.

HIV-1 proteinase is shown to interact with 5'-(methoxyglycinyl-S-(N-methylcarbamoylmethyl))thiophosphat e derivatives of 3'-fluoro-3'-deoxythymidine (FLT), 3'-azido-3'-deoxythymidine (AZT) and of acyclovir (ACV). The enzyme is inhibited in vitro by micromolar concentrations of these compounds. The Ki-value for the FLT derivative was 15 microM. Other closely related 5'-phosphate derivatives of nucleoside analogues tested showed no effect on the enzymatic activity, indicating a high degree of specificity. This type of compound is unstable in buffer at alkaline pH and in cell culture resulting in inhibition of HIV replication. HIV proteinase does not catalyse the hydrolysis nor is it inhibited by the hydrolysis products. Modelling of the non-nucleoside moiety of the compounds show that they can adopt a low energy conformation which is similar to a pseudo C2 symmetric inhibitor of HIV-1 proteinase.

[Orbital metastasis of kidney carcinoma]. / Orbitametastase eines Nierenkarzinoms.

PURPOSE: The case report of a patient with renal cell carcinoma and orbital metastasis is presented and the clinical and histological characteristics are discussed. PATIENT: A 69-year-old man, status post nephrectomy secondary to a renal cell carcinoma, presented with a swelling of the lower lid, reduced visual acuity and visual field defects in the left eye. Ultrasonography and CAT scan revealed a well demarcated orbital tumor. THERAPY: The tumor was excized in toto and the diagnosis orbital metastasis of a renal cell carcinoma verified histologically. The patient showed good postoperative recovery with greatly reduced clinical symptoms. Two years later a recurrence of the orbital tumor was noticed, which was also removed in toto. CONCLUSION: The in toto excision of an orbital metastasis of a renal cell carcinoma is a valid therapeutic approach regarding the tumor morphology and the achievable postoperative symptomatic relief.

The AT-rich sequence of the SV40 control region influences the binding of SV40 T antigen to binding sites II and III.

During lytic infection SV40 T antigen binds specifically to three different regions of the SV40 DNA to initiate DNA replication and to regulate early and late transcription. We constructed plasmids containing either 23-bp synthetic oligonucleotides representing site I or II or SV40 DNA fragments with combinations of binding sites II and III with or without SV40 specific flanking regions. These plasmids were used to determine which sequences are sufficient for specific binding to isolated regions II and III. Under identical conditions T antigen bound in a sensitive in vitro binding assay efficiently to site I but not to the corresponding oligonucleotide of site II. Binding to site II could only be observed in the presence of the adjacent 17-bp AT-rich region of the SV40 DNA. On account of the markedly low affinity for binding site II, T antigen concentrations were required which exceeded those necessary to achieve saturation of binding to site I. The very low affinity for isolated site III could be slightly raised by the same AT-rich region. An increased binding to site II at 37 degrees compared to 0 degree in the presence of this region points to an indirect influence on the DNA structure of the binding site.

[Building blocks for oligonucleotide syntheses with uniformly fragmentable beta-halogenated protective groups]. / Bausteine für Oligonucleotid-Synthesen mit einheitlich fragmentierbaren beta-halogenierten Schutzgruppen.

5'-Dimethoxytrityl-3'-phosphite amides of deoxynucleosides are synthesized. Phosphite/phosphate is protected by the 2,2,2-trichloro-1,1-dimethyl-ethyl (TCB) group, heterocyclic bases by the 2,2,2-trichloro-2,2-dimethyl-ethoxycarbonyl (TCBOC) group. Deoxyguanosine is also blocked by 6-O-trichloroethyl thus avoiding the difficulties observed with monoprotected guanine residues.

Determination of isocyano groups on polymer supports by bromination.

The isocyano content of several cross-linked polymer samples, carrying ca. 0.5-3.0 mmole of isocyanide groups per gram, was determined by reacting the resins with excess of bromine in chloroform, then treating the unreacted bromine with potassium iodide and titrating the liberated iodine with thiosulphate. The method is not suitable for titration of soluble isocyanides, but for the determination of insoluble macromolecular isocyanides is more satisfactory than the thiocyanic acid method.

[Asymmetric synthesis with unlimited stereoselectivity--the synthesis of isomer-free peptide derivatives by stereoselective four-component condensation (author's transl)]. / Asymmetrische Synthesen mit unbegrenzter Stereoselektivität. Die Synthese isomerenfreier Peptid-Derivate mittels stereoselektiver Vierkomponenten-Kondensation.

The development of methods for the synthesis of peptides by stereoselective four-component condensations led to new ways to prepare pure chiral chemical compounds with high yield by asymmetric syntheses. A scheme of asymmetric syntheses is described, which begins with a productively stereoselective synthesis affording a high yield of the desired product, accompanied by a minor amount of a diastereomeric byproduct. This is converted into an easily removable non-isomeric compound by a subsequent reaction with unlimited destructive stereoselectivity which is due to non-linear effects. In general, only small losses of the main product occur during the latter step. The efficiency of such asymmetric syntheses is enhanced by the use of chiral templates which can be recycled. As an illustration we describe the synthesis of a stereoisomer-free tetravaline derivative by a productively stereoselective four-component condensation, followed by conversion of the contaminating diastereoisomer into an easy to remove non-isomeric compound by destructively stereoselective partial acidolysis which yields the main product in 73% and with a purity of greater than 99.98%.