(±)-trans-Dihydronarciclasine and (±)-trans-dihydrolycoricidine analogues modified in their ring A: Evaluation of their anticancer activity and a SAR study.

A series of (±)-trans-dihydronarciclasine and (±)-trans-dihydrolycoricidine derivatives with variously substituted ring A was synthesised and evaluated for their antiproliferative activity against 60 human tumour cell lines (NCI60), representing leukemia, melanoma, and cancers of the lung, colon, brain, ovary, breast, prostate, as well as kidney in vitro. Among the 13 alkaloids screened, (±)-trans-dihydronarciclasine showed the highest potency as a cytotoxic molecule. A structure-activity relationship (SAR) study indicated that the presence of a hydroxy group at position 7 and a rigid, 1,3-benzodioxole scaffold were essential for the antiproliferative activity.

Stereoselective synthesis of trans-dihydronarciclasine derivatives containing a 1,4-benzodioxane moiety.

ABSTRACT: Some new trans-dihydronarciclasine derivatives containing a 1,4-benzodioxane moiety were stereoselectively synthesised using our feasible and efficient method developed recently. These new phenanthridone alkaloid analogues were obtained in both racemic and optically active forms. High enantioselectivities (up to 99% ee) were achieved by applying (8S,9S)-9-amino(9-deoxy)epiquinine as an organocatalyst. Due to a side reaction, various methoxyphenanthridine regioisomers were also prepared which afforded further synthetic trans-dihydronarciclasine analogues modified in the ring A of the phenanthridone scaffold.

The First Enantioselective Total Synthesis of (-)-trans-Dihydronarciclasine.

A feasible and enantioselective total synthesis of (-)-trans-dihydronarciclasine [(-)-1], a highly biologically active alkaloid, was devised starting from vanillin (8). The key step of this new synthesis was an asymmetric, organocatalytic Michael addition, in which an optically active nitropentanone [(-)-13] was obtained from a butenone derivative (12). Excellent enantioselectivity (>99% ee) was achieved using the (8S,9S)-9-amino(9-deoxy)epiquinine (16) organocatalyst. The target molecule can be prepared in 13 steps from compound (-)-13. The total synthesis has provided a facile and first access to the ent-form of naturally occurring (+)-trans-dihydronarciclasine, a highly potent cytostatic alkaloid.

Effects of vasoactive substances on the neurovascular structures and microcirculation in the developing callus 10 and 15 days after bone injury.

The developing callus requires sufficient oxygen and substrate supply. Despite the importance of these processes, we have limited understanding of regulation of the callus microcirculation. We aimed to assess the role of vasoactive substances in the microcirculation of the callus in a gap osteotomy model in the rabbit detected by laser-Doppler flowmetry. The reactions were elicited with locally applied vasoactive substances: epinephrine (E), calcitonine-gene related protein (CGRP), substance P (SP), sodium nitroprusside (SNP) and Ebrantil (Ebr) on the 10th and 15th postoperative days. Changes of the circulatory parameters were compared to changes in the ipsilateral femoral bone marrow. Perfusion pressure, maximal change of the blood flow and 50% recovery time (50RT) of the flow reactions and peripheral micro vascular resistance (MVR) was calculated. Systemic blood pressure (BP) was measured directly with an arterial catheter. Reactive neurovascular structures, sensitive to neuropeptides and vasoactive substances, appear at a very early stage of callus formation. On the 10th postoperative day, 2/3 of the blood flow velocity of the intact tibia has already returned, and the values are higher on the 15th postoperative day than those of the intact tibia. The basal blood flow velocities (prior to administration of any substance) are significantly higher on the 15th postoperative day than on the 10th.

Calcitonin gene-related peptide, substance P, nitric oxide and epinephrine modulate bone marrow micro circulation of the rabbit tibia and femur.

Different bones have different blood supplies, which may influence bone healing. Therefore, elucidation of the mechanisms involved in the regulation of bone marrow blood flow in different bones is of high clinical importance. To assess the micro circulation of bone marrow of the femur and tibia simultaneously, flow velocities were continuously measured by a two-channel laser-Doppler flowmeter. The probes were introduced into the femoral and tibial diaphysis, respectively, in the anesthetized rabbit. Changes in micro circulation of the bone marrow were elicited by intra-arterial bolus injections of vasoactive substances: epinephrine (E), calcitonine-gene related peptide (CGRP), substance P (SP), sodium nitroprusside (SNP), E and Ebrantil. Systemic arterial blood pressure was recorded with an electro-manometer. Micro vascular resistance (MVR) and 50% recovery time (50RT) to baseline flow level were calculated from the measured data. Flow velocity in the femur was significantly higher. Epinephrine considerably reduced micro vascular blood flow, which could be significantly warded off by Ebrantil. CGRP and SP did not change MVR. Application of SNP resulted in reduction of flow velocity, but it also decreased MVR. No statistically significant differences were found between reactions of the micro circulation in the two marrows. These results suggest that there are no significant differences between the blood flow response patterns of these two bone marrow sites, thus the regulation patterns of the micro circulation of the two bones are also similar.

Effects of neuropeptides and vasoactive substances on microcirculation of the callus after tibial osteotomy in rabbits.

Previous studies have demonstrated a dynamic ingrowth of vessels into the developing callus. In this study, maturation and development of the regulation of microcirculation were followed in the callus of rabbits. In the first series, the effects of vasoactive substances on blood flow velocity, perfusion pressure, duration of effects and peripheral vascular resistance of the bone marrow in the femur and tibia were compared. In the second series, the same parameters were measured in the femur and in the developing callus 10 and 15 days following gap osteotomy of the tibia. There were no significant differences between the microcirculatory reactions of the intact femur and tibia. Basal blood flow could be verified in the callus on the 10th postoperative day. No vascular reactions could be elicited. Basal blood flow velocity was higher on the 15th day, when compared to the measurements on the 10th day. The substances elicited statistically significant differences in flow velocity, resistance and 50% recovery time in the callus on the 15th day. Blood flow reactions of the ipsilateral femoral and tibial bone marrow are identical, thus the femur can serve as a reference site for blood flow measurements in the callus. Regulation and maturation of callus microcirculation develop rapidly between the 10th and 15th days.

Changing the treatment to reduce complication rate in open tibial fractures.

Complications of open tibial fractures have been found to be very frequent after application of monotherapies (external fixator, plate, intramedullary nailing). The use of combined therapy has improved our results. We treated 658 patients for open tibial fractures over a course of 15 years. Plating was the method of treatment in the initial phase, and then external fixators and unreamed tibial nails (UTN) were used as a monotherapy. In the last ten years the option of a combined therapy was at our disposal, namely, changing the method of treatment. Monotherapy was performed in 352 cases, and 270 patients were treated in a combined manner. The rate of septic complications could be reduced with the combined therapy from 15.5% to 6.6%, the rate of bone healing disorders from 31.6% to 8.7%, and that of amputations from 4.9% to 0.7%. Elaboration of therapeutic tactics and their consistent application increases the healing potential of open tibial fractures. During this 15 year period, our therapeutic concepts have changed, whereby gradual, combined therapy models were initiated, increasing the advantages and decreasing the disadvantages of the different methods.

Highly enantioselective organocatalytic conjugate addition of nitromethane to benzylidene acetones.

Six active 4-aryl-5-nitro-pentan-2-ones were synthesized enantioselectively from the corresponding 5-aryl-butenones by asymmetric Michael addition of nitromethane using an imidazolidine-type enantioselective organocatalyst. The ee ratio of the products were between 67 and 100%, determined by HPLC with Chiracel OD. Molecular and crystal structure of 3,4-methylenedioxy-phenyl-5-nitro-pentan-2-one has been studied by single crystal X-ray diffraction.