DE10237704A1 - Method and device for the intermolecular transfer of activation energy for bond cleavage through space - Google Patents

Abstract

The present invention relates to a method for breaking chemical bonds, the activation energy for breaking the bond being delivered through space by a carrier molecule which can change from its ground state to an excited state by being irradiated with electromagnetic radiation. The invention further relates to a device for the intermolecular transfer of the activation energy for the bond cleavage of carrier molecules to target molecules which contain the bond to be cleaved, comprising a storage container which contains the carrier molecules, means (113) for transporting the carrier molecules through an activation region ( 104), activating agent (102) and an exchange area (101) containing the target molecule. Furthermore, the present invention relates to the use of the method according to the invention and the execution of the light-controlled in-situ synthesis in 5 'to 3' or 3 'to 5' direction of nucleic acid derivatives on solid supports for the production of biochips or gene chips.

Description

The present invention relates to a method for breaking chemical bonds and a device for the intermolecular transfer of activation energy for bond cleavage and in particular a method for performing nucleic acid synthesis in 5 'after 3' or 3 'after 5' direction. The procedure can be under others for the production of arrays from oligomers, which are used via their 5 'or 3' ends on a support are bound.

• – Erhitzen (thermische Dissoziation). Die Energie zur Bindungsspaltung, wird durch eine externe Quelle thermischer Energie zur Verfügung gestellt.
• – Bestrahlen (photochemische oder photolytische Dissoziation). Die Energie zur Bindungsspaltung wird in Form von Photonen zur Verfügung gestellt.
• – Anlegen eines elektrischen Stroms in einem geeigneten Medium (elektrolytische Dissoziation).

Methods of breaking chemical bonds are well known and are used in chemistry, biochemistry and related technology fields. For example, bond cleavage, also referred to as "homolytic dissociation", is accomplished in molecules by:

• - heating (thermal dissociation). The energy for bond breaking is provided by an external source of thermal energy.
• - irradiation (photochemical or photolytic dissociation). The energy for bond cleavage is provided in the form of photons.
• - Applying an electrical current in a suitable medium (electrolytic dissociation).

The one necessary for bond breaking Energy (the so-called activation energy, comprising the "actual" Binding energy or enthalpy Δ / H) is different for each chemical bond and hangs continue, even for identical bonds, also from the specific chemical Environment of each binding partner.

The photochemical cleavage of chemical bonds or photochemically induced reactions generally require a complicated device structure, especially if they are carried out on a large scale: So that they can be irradiated with the necessary wavelengths Reaction can be brought have to all the reactants involved continue to be in the same reactor or reactor system. The radiation procedure can often also lead to unwanted side reactions and byproducts that the Reduce overall yield and cumbersome cleaning procedures of the products.

This is particularly difficult in the field of light-controlled in-situ synthesis of nucleic acids on solid supports, which is used in the production of so-called biochips or gene chips (nucleic acid chips). Usually two techniques are mainly used for the photolytic in-situ synthesis of nucleic acid derivatives (oligonucleotides) on solid supports. The first method is called a "photolithographic method" using photolithographic masks, such as that described in US Patent No. 5,510,270 is disclosed. This method uses the surface of a solid support to arrange a plurality of so-called “spots”, which are arranged in the form of an array, on a surface of the solid support. Each spot contains a large number of identical nucleic acid fragments. These fragments also carry photolabile protective groups Irradiation of the spots leads to the cleavage of the chemical bond which connects the photolabile protective groups to the nucleic acid derivative. After the protective group has been removed, a reaction with a new protected nucleic acid derivative is possible. The reaction is continued until the nucleic acid chains have their end lengths. In order for scattered light to also reach neighboring spots and consequently to remove protective groups from other target molecules which are not to be removed, masks with a diameter the size of the spots have to be produced, which leads to the cumbersome and costly Finally, the fact that more than 100 of these masks have to be produced in order to produce a biochip with target molecules which have a length of more than 25 nucleotides. This leads to high costs in the above-mentioned synthesis.

An alternative method for light-controlled in situ synthesis of oligonucleotides using photosensitive Protection groups were developed by Bogoslawski, J. (2001), Drug Discovery and Development, 3, pages 15-16 proposed. The usual Masks with holes are created by virtual masks consisting of plates and micromirrors, replaced. The process was called "maskless array synthesis" (MAS). This procedure allows defined arrays on the chip surface with UV light using up to 480,000 micromirrors irradiate.

The U.S. patent 5,472,672 describes a device for polymer synthesis for the synthesis of oligonucleotides, in which the oligonucleotide chain is built up by successive dropwise addition of polymer units in solution on a solid support, preferably in a microtiter well of a microtiter plate. The reagent solution is supplied via a head device, which has a plurality of nozzles. This head device can also take the form of a piezoelectric pump, as described in the US patent 5,474,796 is described. When performing the standard chemistry described above, the polymer units in each well will react to build the oligonucleotide chain. A major disadvantage of this process is the addition of strong acids and bases which attack the material of the head device and which have to be washed out of the well after the reaction has ended.

It was therefore an object of the present invention a new and effective process for breaking chemical bonds, especially for breaking chemical bonds in molecules during the in situ synthesis of oligonucleotides in the production of biochips to disposal to deliver. This task was accomplished through a split process chemical bonds released, the activation energy necessary for the bond cleavage of a selected bond by means of a carrier molecule the room is delivered. This "spatial decoupling" of the activation and reaction process leads to a big one Decrease in unwanted by-products. She continues to lead to eliminate side reactions that are always present when a reaction mixture containing all reactants is irradiated becomes. In the method according to the invention only carries the carrier molecule the activation energy for bond cleavage, the carrier molecule being activated at another location and transfers the necessary activation energy to an area where the photochemical reaction will take place, that is the cleavage selected chemical bonds in a target molecule.

The term “carrier molecule” as used in the present context includes molecules with electrons in energy levels in the ground state that can be excited by radiation energy, the excited electrons being in an energy level of the excited (or activated) state, which is a higher energy than the energy level of the ground state.

The term "excited state" as used herein means any electronic excited state of a molecule. The electron transitions from the basic states to the excited states are called "vibronic" designated because electron transitions from Vibration transitions accompanied become. An “excited State "can be, for example, the triplet state if the ground state is the singlet state, or the singlet state if the Ground state is the triplet state. But also any other basic and excited states of molecules are included in the invention.

There is also an important feature the present invention in that the carrier molecules by interacting with electromagnetic radiation is not destroyed or decomposed.

The term "target molecule" refers to any molecule that in capable of a chemical reaction with a reactant to enter if the for the implementation the activation energy required by the chemical reaction Carrier molecules supplied becomes.

It is preferred that the carrier molecule is in its Ground state and is irradiated before it targets a target is brought into contact to cleave bond. The basic state of a carrier molecule allowed it, other energy states of the carrier molecule to reach which can store the activation energy and this energy on can transfer a target molecule. Includes, of course the scope of the invention molecules that have a singlet or triplet ground state.

In a preferred embodiment According to the invention, the carrier molecule is in one after the irradiation excited state. Usually the excited state has one Lifetime of the excited state that is long enough to reach the Transfer across the room or across a direct physical contact of the excited carrier molecule with one potential target molecule to enable. From the above, it is obvious that carrier molecules unite have excited singlet or triplet state. It is also from the foregoing, it is obvious that the term “more excited State "denotes any excited state of a carrier molecule, that is to say comprehensively its first, second, etc. excited state.

It is particularly preferred that the energy difference between the ground state and an excited one Condition of the carrier molecule at least the same or larger, than the activation energy for bond cleavage, which at least minimal energy to carry out the reaction is delivered.

• a) Aktivieren des Trägermoleküls in einem Aktivierungsbereich durch Bestrahlen des Trägermoleküls,
• b) Transportieren des aktivierten Trägermoleküls aus Schritt a) durch den Raum zu einem Austauschbereich, der ein Zielmolekül umfasst,
• c) Übertragen der Aktivierungsenergie des Trägermoleküls auf ein Zielmolekül in dem Austauschbereich.

In a further particularly preferred embodiment, the method according to the invention comprises the following steps:

• a) activating the carrier molecule in an activation region by irradiating the carrier molecule,
• b) transporting the activated carrier molecule from step a) through the space to an exchange region which comprises a target molecule,
• c) transferring the activation energy of the carrier molecule to a target molecule in the exchange region.

The method according to the invention therefore allows the selective transport of the necessary generated at another location Activation energy to an area where selected target molecules with too cleaving bonds for the reaction can be activated, that is, for a bond cleavage. Therefore goes the activation energy is not lost and the presence of unwanted ones By-products are reduced dramatically.

The term "transfer" in step c) includes any method by which energy transfer from one molecule to another can take place. Typically, direct physical contact from molecule to molecule is sufficient. Other types of transfer are "through space", for example in solution, dispersion, solids etc. via vibration transfer if the molecules are close enough together in space.

It is preferred that the number of the carrier molecules to be activated selectable is. This also allows the specific activation of only a few or a big one Number of target molecules, that are to be made to react.

It is further preferred that the transfer of the carrier molecule to the Exchange area spatially can be controlled. This makes possible, that only a few molecules in a selected one Exchange area can be activated without molecules in neighboring Spots or in a neighboring to the selected exchange area Area to be affected.

The basis of the present invention lying task is further achieved by a device for the intermolecular Transfer of the activation energy for the bond cleavage of carrier molecules to target molecules that have a bond to be split, solved, comprising a storage container which the Carrier molecules includes, agents, around the carrier molecules to the activation area to deliver; Activation agent and an exchange area comprising the target molecule.

The method according to the invention allows one simple device construction, which is not very complicated and enables selective transfer of carrier molecules comprising the stored activation energy, to selected spots of an activation area, without the risk of activating other areas in the exchange area.

The exchange area advantageously comprises a solid support. In another preferred embodiment, the exchange area a reaction vessel. The solid carrier or the reaction vessel is for either UV / VIS radiation permeable or impermeable or it can be translucent.

In another preferred embodiment is the solid carrier for UV / VIS light impermeable. this makes possible an enlargement of the Material selection for the production of the solid support, with the further advantage that also target molecules on the carrier can be attached which is characterized by heat with direct irradiation to initiate a photochemical reaction would decompose because opaque Substrates heat up when exposed to direct radiation.

It is particularly preferred that the solid carrier is movable in one direction, making the precise selection of individual Spots possible which contain target molecules along this direction on the solid support, to which carrier molecules are delivered or supplied should be.

In a further preferred embodiment includes the carrier an array spatially separate regions that encompass the target molecules, creating a simultaneous Building big molecule libraries allows becomes.

It is advantageous that the activation area is located above the exchange area, making the use of gravity for the transfer of the activated carrier molecules to the Exchange area enabled becomes.

In a particularly preferred embodiment the activation area comprises an electromagnetic field Activation of the carrier molecules, the is usually easy to create.

In a further preferred embodiment the device comprises means of transport located above the activation area are arranged to support the carrier molecules Activation area to deliver, which also reduces gravity for the transfer of the carrier molecules used without a complicated structure.

The means of transport are advantageous movable in one direction, preferably perpendicular to the direction of movement the solid support, giving two more degrees of freedom when choosing a single one Spots on the solid support added. Because the directions of movement of the exchange area and If the means of transport are orthogonal to each other, each desired individual spot can be on the solid support selected be and individually with specific and selected quantities and / or volumes of the carrier molecules are supplied.

The object of the present invention is further controlled by a method of executing the light Synthesis in the 5 'to 3' or 3 'to 5' direction of a nucleic acid derivative solved, comprehensively the reaction of selected Nucleosides and / or nucleotides under suitable reaction conditions, the appropriate photolabile protecting groups at their 3 'or 5' O position have, characterized in that a selected carrier molecule a Happens activation area that includes an electromagnetic field before it is transported to an area that is a suitable one Nucleoside and / or nucleotide with a photolabile functional Group includes.

The inventive method allows the selective Deprotection of nucleosides and / or nucleotides, in which only a selected one Number of carrier molecules to the chosen Nucleosides and / or nucleotides is transported to the chain extension reactions only in selected Areas.

The electromagnetic field, which can be temporary or stationary, is advantageously generated by a laser source. Laser sources are well known and readily available, they can provide large amounts of energy within a selected and limited space, they are easy to use and the construction according to the invention does not require high-performance optics and can therefore be inexpensive and miniaturized. Laser light provides a source of coherent, non-scattering monochromatic light is available compared to, for example, light generated by conventional polychromatic, state-of-the-art mercury lamps, the light of which has to be made coherent by means of a complicated apparatus structure.

It is preferred that the carrier molecule be of its Ground state changes to an excited state when there is the electromagnetic field happens and that the lifespan of its excited state more than 0.5 ms, around the activation energy without any loss of energy from that Transport the activation area to the exchange area. The For example, a change from a singlet ground state to one excited triplet state or from a triplet ground state into an excited singlet state.

For it will be apparent to those skilled in the art that the scope of the invention not just those mentioned above Features includes, especially combinations of these and that the scope of the invention also relates to each and every feature the invention described herein comprises.

The invention will be further described in the following description of preferred embodiments with reference to FIG 1 described in detail.

1 shows a schematic structure for a device according to the invention.

1 shows a device 100 which comprises a solid support, which is preferably in the form of a so-called "chip" known to the person skilled in the art, the material of which can be freely selected from those materials known for the intended purpose, such as for example coated glass supports, nylon supports, etc.

The chip 101 represents the exchange area according to the invention and shows a two- or three-dimensional array of spots 125 that encompass the target molecules. The target molecules can be in pure form or contained in a solution or dispersion, etc. They can also be generated in situ or ex situ via sol / gel synthesis.

Typical target molecules include are not limited on protected or unprotected nucleosides or nucleotides comprising 2 to 20 nucleotides, amino acids and their derivatives, oligo- (consisting of 2-9 amino acids), poly- (consisting of 10-100 Amino acids) and macropeptides (consisting of more than 100 amino acids), hydrocarbons and their derivatives, proteins, etc.

The array includes a freely selectable geometric Arrangement, usually with lines arranged orthogonally to each other, consisting of small spots or two- or three-dimensional micro-objects exist. The points. can also porous Structures such as zeolites, monotubes, silicones, siloxanes, etc. include.

Likewise, every other geometric Arrangement within the scope of the invention.

The chip 101 is on an in 1 attached high-resolution stepper device, not shown. Any stepper device capable of holding the chip can be used 101 to move in the desired direction and such stepper devices are basically known to those skilled in the art. The chip 101 can, as shown by the arrow in 1 shown and indicated with the letters C and D, move in one direction. The chip 101 is between a laser source 102 , for example a dye laser, an LED laser or a YAG laser. The laser generates a field of electromagnetic radiation 104 , which represents the activation region according to the invention. The laser 102 opposite are reflective means, for example a mirror 103 or a plurality of mirrors can be attached to reflect the laser light and a large activation area 104 to create.

Above the activation area 104 is a printer head 113 arranged. In another embodiment of the invention, however, is the printer head 113 below the activation area 104 arranged. This arrangement is particularly advantageous when a low surface tension solution / solvent, such as toluene, is used that is not in a region above the activation range 104 attached printer head 113 is retained and would therefore spray onto the substrate in an uncontrolled manner.

The printer head 113 is movable in the directions represented by the arrows and the letters A and B. The direction A to B is in relation to the direction C to D of the chip 101 orthogonal on the stepper device. This structure allows the activated carrier molecules 111 that come from the printer head 113 be sprayed onto one or more selected spots 125 on the surface of the chip 101 to focus and apply. The printer head 113 has an outlet 114 , preferably a nozzle that is adjustable to the volume of the droplets that hit the surface of the chip 101 to be sprayed.

The printer head 113 may include one or a plurality of nozzles. Two important factors affecting the liquid discharge of the carrier molecules through the outlets 114 , particularly affected by nozzles, are: a) how can a droplet be expelled cleanly so that a droplet does not get stuck at the end of the nozzle? b) how to avoid the content of a spot 125 , which includes the target molecules, spatter when the droplets 120 that comprise the carrier molecules on this spot 125 be applied. A person skilled in the art will therefore choose the mode of application of the carrier molecules depending on the type of solution, suspension, etc. len to the droplets 120 which comprise the carrier molecules, in a continuous jet, in a pulse series or in droplet form.

Also a variety of printer heads 113 is within the scope of the invention. Another embodiment of a printer head according to the invention 113 comprises a piezoelectric pump of an arrangement as described in the US patent 5,474,796 is disclosed.

The printer head 113 is with a storage container 110 that the carrier molecules 111 contains, connected. From the above it is obvious that in the presence of a large number of printer heads 113 every single printer head 113 is connected to a storage container, which makes it possible, for example, in each storage container 110 to have a reservoir of different carrier molecules. It is also within the scope of the invention that a variety of printer heads 113 with a single storage container 110 are connected. A further preferred embodiment comprises building blocks for the selective synthesis of oligonucleotide chains in one or more storage containers 110 , so that reactions and chain extension can be carried out simultaneously on different or on identical spots by a suitable choice of the order of ejection of the carrier molecules and building blocks.

The connection 112 is for example any tube or hollow body which is suitable for this purpose and which is essentially known to the person skilled in the art. The connection 112 is preferably flexible and semi-elastic, such as a TEFLON ^® pipe.

The carrier molecules can either be in solution, in pure form or in the form of a suspension or a dispersion within the storage container 110 available.

Representative, non-limiting examples Carrier molecules according to the invention include acridone, Xanthone, thioxanthone, benzene, naphthalenes and their substituted or unsubstituted derivatives, for example N-methylacridone, 2-ethylthioxanthone, 2-anilinonaphthalene, Naphtho [1,2-c] [1,2,5] thiadiazole, benzo [b] fluorene, 5,7-dimethoxy-3-thionylcoumarin, 1,2-cycloheptanedione, 3-acetyl-6-bromo-coumarin, 2-bromo-9-acridinone, 4,4'-dibenzylbiphenyl, 2,6-dithiocaffeine, 1,4-dibromonaphthalene, dibenzo [fg, op] naphthalene, 10-phenyl-9-acridinone, 2-methyl-5-nitroimidazole-1-ethanol, 1- (2-naphthoyl) aziridine, 9- (2-naphthoyl) carbazole, 4,6'-diamino-2-phenylbenzooxazole, p-thiophenyl, 3-acetylphenanthrene, Dinaphtho- [1, 2-b: 2 ', 1' -] - thiophene, (E) -piperylene, β-methyl- (E) styrene, 2-phenylbenzothiazole, quinoxaline, 9,9'-biphenantryl, naphtho- [1,2-c] [1,2,5] oxabiazole, Phenothiazine, 2-ethoxynaphthalene, 9-phenyl-9-stibafluorene, 9,10-antrachinone, 4,4'-dichlorodiphenyl. Other suitable compounds are in S. L. Murov, I. Carmichael and G.L. Hug, Handbook of Photochemistry, Marcel Dekker, Inc., New York 1993.

From the outlet funds 114 of the printer head 113 become little droplets 120 from carrier molecules to the selected spots 125 on the chip 101 pushed out. When passing the activation zone, i.e. the field of electromagnetic radiation 104 , the molecules in the droplets change 120 into an excited state, for example from the singlet state to the excited triplet state, because they are supplied with sufficient energy to enable an energy level transition. It is also within the scope of the invention that all other sources of electromagnetic radiation that can induce energy level transitions in molecules can be used for the purpose of the present invention, for example sources that generate microwaves, infrared or Raman radiation.

The energy "stored" in the molecule in its excited state, for example in its triplet or singlet state, is at least equal to or greater than that for the bond cleavage in the target molecules, that in the spots 125 on the surface of the chip 101 necessary activation energy are included. Specific target molecules are, for example, typical nucleic acid derivatives with NPPOC protective groups or similar protective groups, as are essentially known to the person skilled in the art, but are not limited thereto.

When passing the field of electromagnetic radiation 104 contain the droplets with carrier molecules 120 now the molecules are in their excited state and are in 1 as "excited droplets" 121 shown. These droplets 121 now come with defined spots 125 on the surface of the chip 101 , which contain the protected nucleic acid derivatives (target molecules), in contact and react with the nucleic acid derivatives and remove their protective groups.

The amount of time to remove the protecting group, this means for the Cleaving the bond between the protecting group and the rest Nucleic acid derivative, depends on the type of carrier molecule and Target molecule, the solvents used, the length the transport path of the carrier molecule in its excited state and the reaction atmosphere (a quenching of the excited carrier molecules quite often observed when using an oxygen atmosphere, depending on the type of carrier molecule, the solvent and the oxygen content). In another embodiment of the invention, the target molecules contain functional groups that on contact with the carrier molecules in-situ an acid form, making acid sensitive Protective groups are split off, which are also present in the target molecules could be.

The method according to the invention in combination with the device according to the invention allows the construction of selected oligonucleotide chains only on the selected spots 125 on the surface of the chip 101 , because in a preferred embodiment of the invention each outlet means 114 can be controlled individually. The target molecules are usually in solution. Excess solvent can therefore be pumped off by the chip 101 is placed in a vacuum chamber after the reaction, which also allows the removal of oxygen that could affect energy transfer. In a further preferred embodiment, the spots are 125 arranged in an array of wells in a microtiter plate. The device is preferably designed for the use of a microtiter plate with 96 wells which are aligned in 12 rows with the same spacing. The microtiter plate is preferably made of a chemically inert material, such as polypropylene or the like. From the foregoing, it is of course obvious that any arrangement of rows or columns can be used in the invention.

Compared to a controlled one Light supply in usual photochemical devices are not optical devices and arrangements necessary, whereby none caused by the optics Loss of energy occurs. Furthermore, this structure does not require photolithographic masks and is unrestricted for the mass production of Chips with one. flexible and individual design.

The structure is also suitable for multiplexing by beam splitting and for using multi-channel printer head devices. Furthermore, the method according to the invention in combination with the device has the advantage that there are no cross-couplings between individual micro-locations, that is to say spots 125 , because energy storage can be selected such that the lifetime of the excited state of the carrier molecule is too short, that it can migrate to distant locations, thereby avoiding unwanted and uncontrollable remote activation or reactions.

Claims (27)

Process for breaking chemical bonds, characterized in that the activation energy for breaking bonds is supplied by a carrier molecule through the space. A method according to claim 1, characterized in that the Carrier molecule in his Ground state is irradiated before it is targeted by a target molecule bond to be cleaved is brought into contact. A method according to claim 2, characterized in that after irradiation the carrier molecule in one excited state. Method according to one of the preceding claims, characterized characterized that the energy difference between the ground state and is equal to or higher than the excited state of the carrier molecule, than the activation energy for bond breaking. A method according to claim 4, comprising the following steps: a) Activate the carrier molecule in one Activation area by irradiation of the carrier molecule. b) Transport of the activated carrier molecule from step a) through space to an exchange area that includes a target molecule. c) Transfer the activation energy of the carrier molecule on the target molecule in the exchange area. A method according to claim 5, characterized in that the Activation area and the exchange area apart are arranged. A method according to claim 6, characterized in that the Number of carrier molecules to be activated can be selected. A method according to claim 7, characterized in that the Transport of the carrier molecules to the Exchange area spatially can be controlled. Contraption ( 100 ) for the intermolecular transfer of the activation energy for the bond cleavage of carrier molecules to target molecules with a bond to be cleaved, comprising a storage container ( 110 ), which comprises the carrier molecules, means ( 113 ) to move the carrier molecules into an activation area ( 104 ) to deliver activating agents ( 102 ) and an exchange area encompassing the target molecule ( 101 ). Apparatus according to claim 9, characterized in that the exchange area ( 101 ) comprises a solid support. Apparatus according to claim 10, characterized in that the solid support is impermeable to UV / VIS light. Device according to claim 10 or 11, characterized in that that the solid carrier is movable in one direction. Device according to claim 10 or 12, characterized in that the carrier has an array of spatially separated areas ( 125 ) includes the target molecules. Device according to one of the preceding claims 9 to 13, characterized in that the activation area ( 104 ) above the exchange area ( 101 ) is arranged. Device according to one of the preceding claims 9 to 13, characterized in that the activation area ( 104 ) below the exchange area ( 101 ) is arranged. Device according to one of claims 9 to 15, characterized in that the activation area ( 104 ) includes an electromagnetic field. Device according to claim 16, characterized in that transport means ( 113 ) for delivery of the carrier molecules in the activation area ( 104 ) are arranged above the activation area. Device according to claim 16, characterized in that transport means ( 113 ) for delivery of the carrier molecules in the activation area ( 104 ) are located below the activation area. Device according to claim 17 or 18, characterized in that the transport means ( 113 ) are movable in one direction. Device according to claim 19, characterized in that the directions of movement of the exchange area ( 101 ) and the means of transport ( 113 ) are orthogonal to each other. Device according to claim 20, characterized in that the transport means ( 113 ) Outlet means ( 114 ) to control the spatially controlled transfer of the carrier molecules into the area ( 125 ) have on the carrier. Procedure for implementation the light-controlled synthesis of a nucleic acid derivative in 5 'to 3' or 3 'to 5' direction, comprising the reaction of selected nucleosides and / or nucleotides under suitable reaction conditions, the suitable photolabile Protecting groups at their 3 'or 5' O position, thereby characterized that a selected Carrier molecule one Happens activation area that includes an electromagnetic field before it is transported to an area that is a suitable one Nucleoside and / or nucleotide with a photolabile protecting group includes. A method according to claim 22, characterized in that the electromagnetic field is a stationary field. A method according to claim 22, characterized in that the electromagnetic field is a temporary field. Method according to claim 23 or 24, characterized in that that the electromagnetic field is generated by a laser source. A method according to claim 25, characterized in that the Carrier molecule from its ground state changes to an excited state when it is the electromagnetic Field happens. A method according to claim 26, characterized in that the Carrier molecule has a lifespan excited state of more than 0.5 ms.